Hypertension Flashcards
What is hypertension?
A condition where the blood pressure is elevated to an extent where clinical benefit is obtained by lowering it
What is the text book value for normal blood pressure and what is it measured in?
120/80 mmmercury
What is systolic and diastolic pressure?
S= pressure when heart contracts D= pressure when ventricles relax
Give four consequences of high BP:
Myocardial infarction (heart attack)
Cerebral vascular accident (stroke)
Heart failure
Renal disease
Give four high risk patients for high blood pressure:
Patients with evidence of cardiovascular disease
Elderly
Diabetic
Renal failure
What type of ethnicity experiences more commonly experiences a high BP?
Black Africans + Black Caribbeans
What is primary hypertension caused by and how much hypertension is due to primary?
90-95%- unknown cause however there are risk factors e.g. smoking, gender, age, stress
What is seconday hypertension caused by and how much hypertension is due to secondary?
5-10%- underlying causes e.g. combined oral contraceptives, NSAIDs, steroids, pseudoephedrine
What are the symptoms of high BP?
No symtoms, that’s why screening is important
What is the only type of symptomatic high BP and how high is it?
Malignant hypertension
180/120
What are the symptoms of malignant hypertension?
Confusion, visual loss, headache, coma
Evidence of small vessel damage e.g in eyes/ kidneys/ brain
What are two ways of measuring blood pressure?
Auscultatory detection of Korotkoff sounds with stethoscope (manual)
Oscillometrially (automatic)
What are the two types of sphygmomanometers?
Mercury sphygmomanometer Aneroid sphygmomanometer (the one we used in blood pressure practical)
What are the sounds of systolic and diastolic sounds when measuring blood pressure manually?
S= First repetitive appearance, faint D= When sound disappears completely
Why is it best to measure blood pressure when the patient is standing up AND sitting down?
The BP may drop when standing, postural hypertension
What should be the consequence if the blood pressure of a patient is more than 140/90 but less than 180/120?
Offer ambulatory bp monitoring or home monitoring or come back three separate times
Give two additional investigations assessments when to do when a patient has higher BP:
Assess 10 year cardiovascular risk
End organ damage
What is the value for severe hypertension and what is the consequence:
180/120
Refer/ admit and treat
Medical emergency
What is the value for stage 2 hypertension and what should be the consequence?
160/100
Treatment required
What is the value for stage 1 hypertension and what should be the consequence of this?
140/90
Offer ambulatory (home) BP monitoring
Lifestyle interventions
Assess CV risk and end organ damage
What is the value of normal BP for under 80’s and what is the consequence of this?
Less than 140/90
Reassess every 5 years
What is the value of normal BP for over 80’s?
150/90
What is the target BP value for type 1 diabetics? If evident complications, what should be the alternative value?
140/80- no complications
130/80- with complications
What should be the target BP value for type 2 diabetics?
The same for non diabetics e.g. for under 80’s 140/90
for over 80’s 150/90
What side of the heart pumps deoxygenated blood?
Right
What is the difference between pulmonary circulation and systemic circulation?
Systemic is to the rest of the body, pulmonary is to the heart
Why are arteries elastic?
Allows for stretch and recoil
What are the three layers of the artery and vein and describe each of their composition:
- Tunica Intima- innermost, includes the endothelium and squamous cells
- Tunica Media- middle, many circular smooth muscle and elastin
- Tunica Aventitia- outermost, fibrous connective tissue rich in collagen and elastin
What is the function of the arteries and explain its properties for this:
Rapid transit for blood from heart to organs
- Have a large radius for low resistance to blood flow
- Elastic nature which contains elastin and collagen fibres for elasticity and tensile strength
What is vascular compliance in the arteries?
Act as a pressure reservoir to provide driving force for blood when heart is relaxing
What are the factors that affect the force exerted by blood against a vessel wall?
- volume of blood contained within the vessel
2. compliance of vessel walls
Define is systolic pressure:
Peak pressure exerted by ejected blood against vessel walls during cardiac systole
Define diastolic pressure:
Minimum pressure in arteries when blood is draining off in the vessels down stream
Why is there a higher pressure in systemic circulation compared to pulmonary circulation?
Blood has to go further and also lungs are delicate so less pressure is used.
What are the sounds when measuring blood pressure?
KorotKoff sounds
What is the pulse pressure and how do you calculate it?
Difference between systolic and diastolic pressure
e.g if bp is 120/80, pulse pressure would be 40mmHg
What is mean arterial pressure and how is it calculate?
Average pressure driving blood forward into tissues throughout cardiac cycle
MAP= diastolic pressure + 1/3pulse pressure
e.g. at bp of 120/80 MAP= 80+13=93
What do capillaries do and how do their properties relate to their function?
Site of exchange between blood and surrounding tissue
One cell thick, maximise SA and minimise diffusion distance
Small radius so velocity of blood flow is slow so provides good exchange time
How do molecules move in and out of the capillaries?
Diffusion
Bulk flow- through pores and intracellular clefts
What happens when capillaries lose fluid?
Lymph nodes collect them
What are capillaries surrounded by to aid then when resting and how do they work?
Precapillary sphincters
Contraction of sphincters reduces blood flow
Relaxation of sphincters increases blood flow
What are the functions of the veins and what are its properties related to their function?
Transports blood back to the heart
Large radius so low pressure therefore little resistance to blood
Most of the blood is in the vein
Have valves to maintain a one way flow
Skeletal muscle pump, contraction of muscle squeezes the veins and pushes the blood up
Give five factors that enhance venous return:
- Driving pressure from cardiac contraction
- Sympathetically induced venous vasoconstriction
- Skeletal muscle activity
- Effect on venous valves
- Respiratory activity
What are lymph vessels made of and what is their properties?
Formed by conversion of initial lymphatics
Empty into venous system, where blood enters the right atrium
One way valves at spaced intervals to direct flow to veins
What are the function of lymph vessels?
Return excess filtered fluid that is lost
Defence against disease, have phagocytes
Return of filtered protein
What problems occur is the lymph vessels go wrong?
Oedema, swelling of the tissues when too much interstitial fluid accumulates
What is smooth muscle contraction due to and how does this work?
Increase in Ca2+ ions in the cytoplasm
Ca2+ binds to calmodulin which activates myosin light chain kinase which phosphorylates myosin leading to myosin power-stroke, leading to smooth muscle contraction
What is shear stress and what is it detected by?
The frictional force parallel to the wall at the surface of the endothelium directly related to blood flow velocity
It is detected by receptors on the endothelial cell which activates nitric oxide synthase and therefore stimulates NO production
How does nitric oxide (NO) cause smooth muscle relaxation?
NO diffuses through the inter membrane space and activates soluble guanylyl cyclase
This increases GMP so protein kinases causes smooth muscle relaxation
How is Mean Arterial Pressure calculated?
Cardiac output x peripheral resistance
What hormones can influence arterial radius?
Adrenal medullary hormones: -Adrenaline and Noradrenaline -Adrenoreceptors Alpha 1= contraction Beta 2= relaxation
What are two potent vasoconstrictors and what do they control?
Vasopressin and angiotensin 2
Important in controlling fluid balance
What are two factors that can have an affect on total peripheral resistance?
Arterial radius
Blood viscosity- not in this module
What are the functions of the arterioles and how does its structure help carry out its function?
Determines the relative blood flow to organs
Small enough radius to offer considerable resistance but large enough to carry blood
Major factor in mean arterial pressure
What is the part of the body where the blood supply always remains constant?
Brain
What are two local chemical influences on arterial radius?
Local metabolic changes
Histamine release
What are two local physical influences on arterial radius?
Local application to hot or cold
Myogenic response to stretch
What are the four types of muscle tissue?
Striated
Cardiac
Skeletal
Smooth
What are the steps in the actin-myosin force generation?
- Myosin cross bridge attaches to actin myofilament
- Powerstroke, myosin head pivots and bends as it pulls one. the actin filament, pulling towards the M- line
- New ATP attaches to the myosin head, the cross bridge detaches
- As ATP-> ADP+Pi, cocking of the myosin head occurs
What is the mechanism of action using Ca2+ ions to create muscle tension?
When Ca2+ enters the cell the intracellular concentration increases and Ca2+ is released from the sarcoplasmic reticulum
Ca2+ binds to calmodulin (CaM) x4
Ca2+ - calmodulin activates myosin light chain kinase (MLCK)
MLCK phosphorylates light chains in myosin heads and increases myosin ATPase activity
Active myosin cross bridges slide along actin and create muscle tension
What is the name for pressure sensors?
Baroreceptors
How is Cardiac Output (CO) calculated?
CO=HR x SV
What is stroke volume and how is it controlled by?
Volume of blood in one heart beat
It is controlled by the venous return
What are the short term control adjustments of baroreceptors?
Occur within seconds
Mediated by autonomic NS
Influences on heart, veins and arterioles
What are the long term control adjustments of baroreceptors?
Require minutes to days
Involve adjusting total blood volume by restoring normal salt and water balance, by urine output and thirst
What are chemoreceptors sensitive to?
Low O2 and high acidity levels in the blood
What is the blood pressure value for hypotension?
Below 100/60 mmHg
When does hypotension occur?
When there is too little blood to fill the vessels
Heart is too weak to drive the blood
What is orthostatic (postural) hypotension?
Insufficient compensatory responses to gravitational shifts in blood when person moves from horizontal to vertical position
Name the two atrioventricular valves and what are they composed of?
Bicuspid(mitral) valves
Tricuspid valves
Supported by chordae tendineae, papillary muscles contract with ventricles to prevent back flow
What are the pulmonary and aortic valves and describe how they work:
Semilunar, half moon
Three cusps
Evertion prevented by upturned nature and positioning of cusps
Close under back pressure
What is diastole and describe it?
Heart relaxing and filling, isovolumetric relaxation
AV valves closed and pulmonary aortic valves closed
As diastole proceeds the weight of the blood will open the AV valves and aortic and pulmonary valves still closed
Blood moves from atria to ventricles
What is systole and describe it?
Contraction and emptying of the heart
AV valves and aortic and pulmonary valves are closed
Ventricles contract
AV valves still closed to prevent back flow but aortic and pulmonary valves open as blood is pushed from ventricles to aortic and pulmonary arteries
What is the equation to calculate stroke volume?
End diastolic volume- end systolic volume
What sac is the heart surrounded by and give its structures and functions?
Pericardial sac
Double walled, tough covering
Anchors the heart
Has pericardial fluid which lubricates the heart and stops it from rubbing at ribcage and other tissues
What is pericarditis?
When the pericardial fluid becomes infected, virally or bacterially, and there is painful rubbing
State and describe the three layers of the heart wall:
Endothelium and endocardium- inner layer which lines the entire circulatory system, barrier between blood and underlying tissue
Myocardium- forms sheets which wraps around the heart, which drives contraction
Epicardium- outer layer, made up of connective tissue
What is the blood supply to the heart called?
Coronary arteries
What type of muscle is the heart made of?
Striated, in branches
What are cardiac muscle fibres interconnected by, describe these connections:
Intercalated discs
Desmosomes- mechanical
Gap junctions- electrical
What is the sarcomere?
A functional contractile unit made up by myosin and actin filament
What is the strength of a sarcomere contraction, and what is it called?
Small force but many of them
End of sarcomere has a Z line, when contracts the Z lines moves closer together
Describe the process for using Ca2+ for contractile function of the cardiomyosite:
Ca2+ binds to uranium receptor on sarcoplasmic reticulum
Ca2+ enters the cytoplasm and binds to troponin, this activates myosin contraction by changing conformation of actin
Ca2+ reabsorbed by sarcoplasmic reticulum by ion channel pump SERCA
What is cardiac output and what is the average CO?
Volume of blood pumped per ventricle per minute
4900 ml/ min
How is heart rate controlled and how does it work?
By the sinoatrial (SA) node (pacemaker)
This SA node reaches a threshold resulting in action potential which spreads through the heart which induces the heart to contract ( have a heart beat)
What type of hormones act on the SA node and consequently do what to the heart rate?
Increase in plasma adrenaline, noradrenaline and epinephrine increase HR
What is preload?
Volume of blood in the ventricles at the end of diastole ( end diastolic pressure)
What is afterload?
Resistance left ventricle must overcome to circulate blood
What are the three things that can affect stroke volume?
Changes in venous return (intrinsic control)
Changes in sympathetic stimulation (extrinsic control)
changes in after load ( disease)
What happens to the stroke volume if end diastolic volume is increased and why?
Increases as stretch of cardiomyocytes stretch more
What is intrinsic activity?
Purely due to the makeup of the heart, more blood in= more blood out
What is the Frank Starling curve?
More blood in in diastolic, more blood out in stroke
How can sympathetic stimulation increase stroke volume?
Activates B1 adrenoreceptors in cardiomyocytes which increases cardiomyocytes contractility so increases strength in contraction. This increases Ca2+ so greater actin-myosin cross-bridge
This is independent of end diastolic volume and only changes sv
How would you calculate the ejection fraction and what is the normal percentage and the failing %?
SV/EDV
Normal= 50-70% or fit people 90%
Failing heart= 30%
How does after load have an affect on stroke volume?
Afterload is arterial blood pressure, so if arterial BP increases, the workload increases due to the elevated BP because of the narrowing arteries which becomes blocked (stenoticexit valve)
conpensation by enlarging cardiac muscles to oppose this but in older weaker hearts this can lead to heart failure
What are two things Angiotensin II can regulate?
Cardiac output
Total peripheral resistance
Where is Angiotensinogen released from and what does it do?
Realeased from the liver
Can be cleaved to form Angiotensin I
Where and when is Renin released, and what does it do?
Renin is released from the kidney (maculadensa) when there is a drop in blood pressure/ fluid volume
It cleaves angiotensingoen to form angiotensin I
What does ACE stand for and where is it released from?
Angiotensin- converting enzyme, released from the lungs
What does ACE do and how does it do this?
Membrane bound protein on the endothelial cells, so as angiotensin I passes across the endothelial membrane it cleaves the inactive angiotensin I to the active angiotensin II
What are two things angiotensin II can do to increase BP?
- Act directly on the blood vessels (smooth muscles), stimulating vasoconstriction
- Act on adrenal glands to stimulate the release of aldosterone
What does aldosterone do?
Acts on the nephron to stimulate the increase reabsorption of salt (NACl) and water from the urine to the blood.
How does noradrenaline increase BP?
Vasoconstriction
How does Angiotensin II cause vasoconstriction?
When Angiotensin II binds to an AT1 receptor, vasoconstriction occurs due to contraction of the smooth muscle cells which causes vasoconstriction and increase in blood volume
AT1 receptor increases Ca2+ conc
How does angiotensin II cause vasodilation?
Angiotensin II binds to an AT2 receptor found on smooth muscles
Give one pathway of the AT1 receptor GPCR reaction to cause vasoconstriction:
AT1 receptor is coupled with Gaq G-protein
When angiotensin II binds, Gaq activates phospholipase C which cleaves PIP2 into DAG AND IP3
IP3 binds to the sarcoplasmic reticulum and this opens Ca2+ channels so ions out of store
Ca2+ in the cytoplasm binds to calmodulin which activates myosin light chain kinase and therefore phosphorylates it
This activates a myosin power stroke which increases smooth muscle contraction and there for increases vasoconstriction and BP
Give the second pathway of the AT1 receptor GPCR reaction to cause vasoconstriction:
After angiotensin II binds to the AT1 receptor, Gaq activates phospholipase C, which cleaves PIP to IP3 and DAG
IP3 binds to the sarcoplasmic reticulum and opens Ca2+ channels so the ions are out of the store into the cytoplasm
These Ca2+ ions activate JAK2 and so a G protein RhoA is activated
Another signalling pathway Rho Kinase ROK 1 and 2 so this leads to phosphorylation and inactivation of myosin light chain phosphatase, which inhibits the dephosphorylate of myosin light chain which increases phosphorylation levels
This increases smooth muscle contraction and vasoconstriction
What is the process for how aldosterone increases BP?
Aldosterone binds with a cytoplasm receptor
Hormone- receptor complex initiates transcription in the nucleus
New protein channels and pumps (that are responsible for Na+ reabsorption and K+ secretion) are made
Aldosterone induced proteins modify existing proteins and this increases the movement of ions and increases the movement of H2O from urine into blood as water flows with the Na+ ions
Why is using aldosterone to increase BP a slower process than angiotensin pathways?
Has to go through transcription
Which channels are used for the aldosterone Na+ reabsorption?
ENaC channels
Which channels are used for the aldosterone K+ secretion?
ROMK channels
What are three pharmacological interventions that can oppose increasing BP?
- Direct renin inhibitor
- ACE inhibitors
- Angiotensin II type 1 receptor blockers (antagonists)
Why is ACE a metal-protease?
Needs a co ordination bond with zinc as it has zinc in its A/S
How do renin inhibitors work and give an example:
Not often used alone
Reduce plasma renin activity
Aliskiren- indicated for hypertension alone or in combination
What is Bradykinin and what does it do?
A potent vasodilator when bradykinin is broken down
ACE inhibits the break down of bradykinin as it induces vasodilation on BK1 receptors on the endothelial cells which stimulate NO
Where is ACE placed to suit its function?
Faces out into the blood
Give an example of an ACE inhibitor and how does it work?
Lisinopril, prevents the conversion of Angiotensin I to II so II is reduced and the rest of the pathway is inhibited
Bradykinin is also able to be stabilised and increase vasodilation
What are other ways in how ACE inhibitors work?
Reduce cardiac load so the heart won’t have to pump so hard
Reduce salt retention and vascular growth so preload is reduced
Preferentially acts on kidney, heart, brain and vascular bends
How do Angiotensin II type 1 receptor blockers (ARB’s) work?
Inhibit AT1 receptors and decrease BP as prevent angiotensin from activating vascular smooth muscle cells to constrict
AT2 receptors are still active is affects vasodilation via NO and bradykinin pathways
Give two examples of ARB’s:
Losartan
Valsartan
What are the benefits of ARB’s compared to ACE inhibitors?
More effective as don’t inhibit the breakdown of bradykinin and other kinins fewer side effects then an ACE inhibitor such as a dry cough
How does Renin cleave angiotensinogen to angiotensin I?
Recognises the amide bond between 10 (leucine) and 11 (valine) and cleaves between them
How does ACE cleave angiotensin I to angiotensin II?
Recognises the amide bond between 8 (phenylalanine) and 9 (histidine) and cleaves between them
What converts Angiotensin II to Angiotensin III and how?
Amino-peptidases- recognises amide bond between 1 (aspartic acid) and 2 (arginine) and cleaves bond between them
How would the inhibition of amino peptidases increase blood pressure?
Stop converting angiotensin II to III. Angiotensin II increases BP more as it’s more active so less would be converted to III and activity of II would increase.
What type of protease is Renin?
Aspartyl protease
What are the three main types of ACE inhibitors and give an example of each:
- Sulfahydryl inhibitors- Captopril (not used anymore)
- Dicarboxylate inhibitors- Enalapril
- Phosphonate inhibitors- Fosinopril
What three factors do you need to consider when designing an inhibitor?
- Structure of the enzyme
- Structure of the natural substrate
- Structure of the inhibitor
Give information about initial inhibitors to lower blood pressure:
Venom boy South American pit viper lowered BP
Does this by potentiates the action of Bradykinin
e.g. Teprotide- effective in IV but not orally, lots of prolene’s, suggests its important
What are mettaloproteases?
e. g carboxypeptidase, three main binding interactions:
- negative charge of peptide sub binds to a + charge in protein (arg)
- hydrophobic pocket
- a zinc atom close to the labile bond which stabilises the intermediate
What does carboxypeptidase A do to work as ACE?
Removes final a.a from carboxyl terminus
What is the difference between ACE and an inhibitor?
ACE removes the last two a.a from the carboxyl terminus, the inhibitor doesn’t do this
Give three sulfahydryl ACE inhibitors?
Succinyl Proline- changing a.a from proline reduces activity
2-methyl succinyl proline
Catopril
What type of drug is Enalapril and what does this mean?
Pro-drug of an ester, no activity outside the body, must be hydrolysed in body to activate drug
Have N containing ring
Name four -Pril drugs:
Quinapril
Lisinopril
Perindopril
Ramipril
What are dual action enzyme inhibitors?
Atrial natriuretic peptide, leads to increases Na+ excretion and a decrease in BP
What are the problems with ACE inhibitors?
Dry cough
Caused by inhibition of break down of Bradykinin, where high levels of it are found in the lung
Why would it be good to use peptide mimics rather than peptides?
Peptides have low bioavailability orally
What are two advantages of using angiotensin antagonists?
No effect on bradykinin degradation
AT1 selective
Give the first Angiotensin antagonist and its features:
Losartan- not a pro drug so readily metabolised
Add a bioisostere, tetrazole group for +ve charge on a.a means an ionic interaction
More lipophilic and good bioavailability
Hydrophobic pocket for lipophilic halogen and alkyl chain
Name two other Angiotensin antagonists:
Valsartan and Irbesartan
Name five types of CaV channels:
L- Type (1) P/Q- Type (2.2) N- Type (2.1) R- Type (2.3) T- Type (3)
What are the three types of calcium channel blockers that act on L- type?
What do they bind to?
- Phenylakylamines- verapamil (heart)
- Dihydropryidines- Nifedipine (hypertension)
- Benzothiazepines- Diltiazem
All binding to the a1 subunit
What are some side effects of calcium channel blockers and why?
Flushing, headaches, ankle swelling, constipation
Due to the blocking of CaV channels in other places
Where do different calcium channel blockers bind?
- Verapamil (heart) - IVS6
- Dihydropryidines- domains IIIS5, IIIS6, IV
- Diltiazem - Cytoplasmic loops joining III to IV segments controlling sensitivity to drugs
Why should you not give a black African Caribbean or a person aged over 55 an ACE inhibitor or ARB as a first line treatment for hypertension?
Due to them not producing enough renin, so its better not to involve the renin- angiotensin system
