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BMS 109 > CDL3 > Flashcards

CDL3 Flashcards

1
Q

L side of the heart makes up the ….circulation, R side the..?

A

Left- systemic (thicker)

Right-pulmonary

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2
Q

Systemic circulation pressure in aorta?

A

120mmHg (systemic systolic BP) high pressure- to whole body

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3
Q

Pulmonary ciculation pressure in pulmonary artery?

A

15-30mmHg- lower blood pressure- only to lungs and needs to slow for gaseous exchange and not damage lungs. (check?)

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4
Q

Pulmonary hypertension threshold? Measure?

A

mPAP greater than 25mmHg. (mean Pulmonary arteriole pressure).
Cathater into to measure.

Pulmonary arterial hypertension also requires:
PAWP / LVEDP ≤ 15 mm Hg
and PVR > 3 Woods Units
(> 240 dyn.sec.cm-5)

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5
Q

Causes of increased mPAP in PH? (4)

A
  1. Shunting of systemic blood pressure- if hole in heart higher pressure systemic blood shunted from L-R (increase pressure)
  2. Thrombus formation ‘pulmonary embolism- lodged blocking pulmonary artery (increases pressure)
  3. Sustained pulmonary vasconstriction- in lungs, vessels- narrows blood flow, icreasesresistance (afterload) , heart has to work harder, BP increased.
  4. Pulmonary vascular remodelling- prolonged vasoconstriction can cause vascular remodelling from healthy to proliferative.
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6
Q

Consequences of pulmonary hypertension?

A
  1. Right ventricular hypertrophy due to increased of work heart
  2. Right heart failure- needs more O2 etc,
  3. Death within 2.8 years average if untreated, arount 7 years with treatment.
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7
Q

Classic case study for a patient with PH?

A

24year old female. Progressive exertional breathlessness and chest pains. Syncopal episodes after exercise.

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8
Q

After classic case study symptoms seen what tests are done?

A

ECG- any R heart strain? T wave inversion?
Echocardiogram- High pulomary systemic Pressure?
Chest Xray- R hypertrophy?
Lung function tests- Normal lung volumes?(else could be due to lungs)

R heart catheterisation. Through jugular vein- move down atria into ventricles and into pulmonary artery- measuring pressures.

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9
Q

PVR in PH patients?

A

Pulmonary vascular resistance

Normal aorund 100dyness but PH can rise to 400-800dyness.

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10
Q

Mean pulmonary arteriole pressure=

A

Mean pressure 2/3 diastolc +1/3 systolic pressure

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11
Q

Pulmonary Vascular Resistance=

A

mPAP-PAWP/Cardiac Output

mPAP- mean pulmonary arterial pressure
PAWP- pulmonary wedge pressure (esimate small arteriole pressure- so mPAP-PAWP indicates pressure difference)

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12
Q

How can you measure PAWP?

A

Pulmonary arterial wedge pressure. Insert a pulmonary cathater with an inflated balloon into pulmonary artery and blood flow pushes it into a small pulmonary arteriole branch to estimate the pressure. Estimation of L atrial/ventricular pressure (preload)

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13
Q

For Pulmonary arterial hypertension thresholds?

A

mPAP greater than 25mmHg. (mean Pulmonary arteriole pressure).

Pulmonary arterial hypertension also requires:
PAWP / LVEDP ≤ 15 mm Hg (if this is raised likely due to other factors e.g. the L side having to work harder and pushing on the R side.
and PVR > 3 Woods Units
(> 240 dyn.sec.cm-5)

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14
Q

Cost of PH treatment?

A

£30-100,000 per person per year

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15
Q

PH Threshold debate?

A

Above 20mmHg mPAP as will go on to develop PH? More research needed

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16
Q

Subgroups of PH? (5- treatable?)

A
  1. Pulmonary arterial hypertension- treatment available.
    2 PH due to Pulmonary embolism- yes- remove surgery
  2. PH due to lung disease COPD- no treatment
  3. Multifactorial/unclear- no
  4. L heart dysfunction - no
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17
Q

Surgery treatment for which type of PH?

A

Chronic thromboemolic PH- thrombus blocking vessel Can remove unless multiple distal.
Can drain the blood, open the vessel and remove the thrombus.

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18
Q

What is pulmonary arterial hypertension?

A

The version we learnt about. Remodelling of vessels and vasoconstriction causes the lumen size to reduce, and so the pulmonary vascular resistance to increase.

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19
Q

Pulmonary arterial hypertension causes?

A

Idiopathic (40%)
Heritated (10%) e.g BMPR2 mutation
x4 times more common in females than males (often 20’s)
40% have PAH mainly due to Connective tissue disease and Chronic heart disease.
1980’s diet pills- 25-50% of incidences due to.

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20
Q

Pathogenesis of PAH (large scale) in lungs?

A

Progressive. Gradually more and more vessels in the lungs become stiff and blocked, use of collateral vessels initially until these become blocked and gradually more and more blocked off vessels, resistance increases and therefore pressure.
Patients can lose 2/3 of pulmonary tree before symptoms.

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21
Q

6 steps of PAH formation?

A
  1. Regulated EC lay on an elastic lamina with VSMC’s below.
  2. Sustained pulmonary constriction due to external factors causes ruffling of ECs ( uncontrolled proliferation and pro-apoptotic), and this damage allows serum leak.
  3. Serum can leak across the elastic lamina. e.g. SM mitogens from ECM storage sites, GF’s and inflammatory mediators such as ET-1, proteases, elastinases, NO dysfunction, thromboxane A2 etc. CONSTRICTION.
  4. The elastin breaks down by elastin peptides released by VSMCs in response to serum. LEAKY. Stiff. These peptides stimulate the production of fibronectin which alters SMCs shape from contractile to motile.
  5. Smooth muscle proliferation (concentric hypertrophy) and then migration (plexiform lesions- remodelled)- lumen v small.
  6. Occluded small vessels, collaterals used but progressive disease so more and more blocked.
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22
Q

Difference between the two lesion stages of PAH?

A

Concentric lesions: Highly proliferative EC and VSMCs and gaps in epithelial cells with inflammatory cells in, but all within their layers still. Apoptose and proliferate

Plexiform lesion: VSMCs migrated up into EC layer chaotic, EC apoptotic resistant.

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23
Q

Cost to sequence genome now vs 15 years ago?

A

$100M to $1000-

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24
Q

Genetic part of PAH? (2)

A

15 genes have been detected to be involved.

e. g. BMPR2 mutations can cause PAH, which is a TGFB receptor. Binding causes the phosphorylation of smad 8 which activated SMAD 4 and activates TF’s chnaging gene expression.
- 80% of HPAH and 20% IPAH due to.

Or BMP9 another ligand to BMPR2- increases receptor count protects endothelium from apoptosis retaining the impermeability. Decreases R ventricular systolic pressure.

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25
Q

Primary type of drugs for PAH? Examples (6)

A

Vasodilators.

e.g. Ca channel blockers, nitric oxide donors, Endothelin R antagonists, PDE5 inhibitors,Prostacyclin derivatives

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26
Q

CCBs for PAH?

A

calcium channel blockers are only effective in patients with acute response to vasodilators (can test in clinic add NO, catheter in heart Right, see if mPAP reduces by 10mmHg- around 10%).
If do respond- good can survive 20+ years on.

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27
Q

Negative impacts of CCBs?

A

sytemic hypotension, bradycardia, periphery oedema.

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28
Q

3 main pathways targetted by drugs for PAH?

A
  • Endothelin to ETA/B-PLC Gq- IP3- increases Ca- CONSTRICTION (inhibit)
  • NO- Soluble GC- cGMP- reduces Ca and activates PKG DILATION (promote)
  • Prostaglandin 2- IP- AC- CAMP- reduce Ca and PKA- DILATION (promote)
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29
Q

PDE5 inhibitors for PAH?

A

E.g. Sildenafil
CAMP and cGMP is broken down by PDE5, so if inhibit this prolong the impacts of cAMP and cGMP which reduce Ca and activate PKG (gmp) and PKA (camp) which causes vasodilation.
First line action with ETA/B antagonists also.
Avoid with nitrates drops systemic pressure too low.

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30
Q

PDE5 inhibitors side effects?

A

flushing, headaches, colour vision change, nose bleeds, persistant erection, neuropathy.

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31
Q

Endothelin receptor antagonists for PAH?

A

E.g. Bosentan, Maciltentan, Ambrientan. (oral)
Blocks ET A/B which causes VSMC contraction and proliferation and extravascularisaion and inflammation of EC.
Added to PDE5 inhibitor early.

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32
Q

Endothelin receptor antagonists side effects?

A

Abnormal liver function, headache, nasopharyngitis, periphery oedema, anaemia.

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33
Q

Macitentan? Trial?

A

Enothelin R antagonist for PAH:
Has slower R dissociation rate, and greater lipid solubility and therefore increased tissue penetration.
SERAPHIN Trial: delayed clinical worsening measured by walking distance before breathlessness.
But continuous ET-1 stimulation overcomes the receptor blocking.

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34
Q

Nitric oxide donors for PAH? Side effects?

A

Riociguat- if have low NO, this stimulates GC bypassing NO need. Lincenced but not for use with PDE5 inhibitors- vasodilate too much.

Diarrhoaea, indigestion, loss of vapillaries in the gut

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35
Q

Prostacyclin derivatives for PAH? Examples.

A

Epoprostenol (Flolan): i.v.
Iloprost (Ventavis): inhaled
Treprostinil (Remodulin): s.c. or i.v.
Beraprost (Japan & Korea only): oral

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36
Q

Prostacyclin derivatives for PAH pharmacology?

A

Use in advanced stages.

COX converts arachidonic acid into prostaglandin H2 (which is converted into many active prostaglandins. These cause dilation through Ip-AC- CAMP-PKA.
These cause dilation of pulmonary and systemic arteriole vessels. This decreases PAP and PVR, reducing afterload.
Also inhibits pulmonary SMCs proliferation in vitro. (no evidence of in vivo)

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37
Q

Struggle with prostacyclin derivatives timing?

A

Producing a stable analogue has been difficult as body broken down quickly- half life 2minutes.
iloprost- 20-30mins
Beraprost- 40-60mins
treprostinil 180-270mins. (oral or IV)

So needs continual use- can have a pump deliver but risk of infection, thrombosis, keeping cool and need to make up daily. (£100k patient each year).
or inhaled form 6-9 times a day (30mins a time) compliance problems and therapy stopped overnight.

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38
Q

Struggle with prostacyclin derivatives specificity?

A

Bind to other receptors also, giving off target effects e.g. diarrhoea, flushing, headache. Tolerance also.

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39
Q

Prostacyclin derivatives PAH option for overcoming short half life? (1-T)

A

Treprostinil 180-270mins half life.
Subcutaneous patch.
Redness of skin, site pain, irritation- pill under skin, increase in fibrosis of skin here- decrease in elasticity.

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40
Q

Problems with prostacyclin therapy? (6)

A 
Development of tolerance
Side effects (diarrhoea, flushing, headache)
Cost (close to £100K per yr per patient)
Need for continuous delivery system
Line related complications 
(infection, thrombosis, pump failure)
Has to be made up daily & kept cold
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41
Q

Prostacyclin derivatives PAH option for overcoming short half life being researched? (2-S)

A

Selexipag- novel oral non prostanoid IPR agonist in phase III trials. Half life is 8hours.
Problem: there are multiple PG receptors, this only blocks one, which is both good and bad- there are some beneficial impacts of the other receptors (in lung EP2) but some of these also cause constriction ( EP1 gut and EP3 in lungs inhibit AC- may downregulate IP receptors maybe).

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42
Q

PH other treatments? (5)

A
  1. Anticoagulants to increase the clotting risks especially for patients on IV or who have chronic thromboembolic pulmonary hypertension.
  2. Oxygen- when have COPD.
  3. Duiretics- reduce oedema due to R heart failure.
  4. sex hormone inhibitors
  5. Elastase inhibitors
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43
Q

PH sex hormones?

A

Research into why x4 more likely in females.
Aromatase involved in production of oestrogen. If block this, positive impact on PAH seen. Oestrogen and BMP cross talk- link with this?

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44
Q

Genetic therapy for PAH?

A

FK506- if transfect a reporter line to express- induced BMPR2 signalling, increases P SMAD.
reduced RVSP and lung pressures in mice.

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45
Q

Elastase inhibitors for PAH?

A

Elafin is reduced in PAH which is a type of elastin. Elastases actively cleave Elastin- toxic to the cells causing inflammation, apoptosis and compensatory proliferation. Inhibtors to increase elastase- phase 1 clinical trials for, but off target effects.

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46
Q

3 layers of an arterial blood vessel?

A

Tunica externa/ Adventia: connective tissue and Vaso verosum.
Media: SMC and external elastic.
Intima: Endothelium+internal elastic lamina. 1 cell thick can be thickened.

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47
Q

Is inflammation of the arterial blood vessels good or bad?

A

Either.
Good inflammation is response to pathogens, parasites, tumour wound healing (scar formation).
Bad: Atherosclerosis, Restenosis, Rheumatoid arthritis etc

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48
Q

What is restenosis?

A

Can happen after treatment (intervention) for atherosclerosis.

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49
Q

Risks with atherosclerosis?

A

Principal cause of health attack, stroke, and gangrene of exteemities. Risk of rupturing- thrombus formation and occluding a blood vessel causng death.

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50
Q

What is atherosclerosis?

A

Hardening stiffening of arteries by plaque formation, due to lipid build up in the walls after initial dysfunction of endothelium causing inflammation.
A nectrotic core, with a fibrous plaque (SMCs and EXC M)

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51
Q

Main risk factors for atherosclerosis?

A

modifiable/lifestyle: diet, smoke, alcohol, obesity, stress, physical inactivity, hypertension, diabtes, dyslipidaemia
Medical/ NOn modifiable: inflammation, age, gender (male), genetics,family history of CVD.
Other: turbulent blood flow bifications haemodynamics.

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52
Q

What can cause high cholesterol levels?

A

Mainly bad diet etc, but can have familial hypercholesteraemia, which is inherited and can occur at birth.

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53
Q

Atherosclerosis age?

A

Can come on in childhood with people with FH, else mainly an aging disease, builds up with age. Mostly asymptomatic until late stages.

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54
Q

Atherosclerosis where and haemodynamics?

A

MOST COMMON PERIPHERY/CORONARY ARTERIES- bifications.
Constant high stress blood on the endothelium will activate eNOS and increase Nitric Oxide release in endothelial cells. This will act upon SMCs and vasodilate, and activate atheroprotective factors. Whereas turbulent flow activated atherogenic impacts e.g. upregulating adhesion molecules on EC, ROS, Cytokine upregulation- chemokine gradient promotes WBC migration, promotion of LDL infiltration.

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55
Q

Virchow suggested?

A

Suggested that atherosclerosis was initiated by injury to endothelial cells- endothelial dysfunction and inflammation. Russell Ross built upon this idea also. Whereas Leonardo Da Vinci saw it as only a lipid storage disease where the plaque ‘absorbing increased nourishment from the blood’

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56
Q

How do Activated endothelial cells leak WBCs?

A

Activated endothelial cells upregulate V-CAM1 and I-CAM1 adhesion molecules. Monocytes/ WBCs bind and roll along the endothelial wall untilt the have firm adhesion. The inflammatory mediators create a chemoattractive gradient (cytokines, GFs)to promote internalisation of monocytes (transmigration). (under inflammation e.g. IL-1 differentiates into macrophages).
ATHEROSCLEROSIS here.

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57
Q

Cholesterol is carried around in the blood in what?

A

liposomes carry cholesterol around in the bloodstream as it is hydrophobic in nature.

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58
Q

LDL migration into the vessel wall?

A

Accumulation of LDL-C causes the migration into the vessel wall. EC’s and macrophages generate ROS. By ROS these are oxidated Ox-LDL.
This is engulfed by macrophages to form foam cells. Foam cells are lipid filled cells which release more inflammatory cytokines, attracting more macrophages etc.

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59
Q

atherosclerosis cytokine examples?

A

IL-1, 6, 8 IFN-Y, TGFB.

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60
Q

Atherosclerosis fibrous plaque?

A

SMCs proliferate and make up the fibrous plaque. This can pertrude and occlude the blood vessel. This is weakened by SMCs and foam cells which degrade the collagen and make the plaque more susceptable to rupture.

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61
Q

After plaque rupture what can happen?

A

In the event of rupture, coagulants are released and this increases the likelihood of thrombus formation here. This can detatch and occlude a blood vessel- MI or stroke/ death

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62
Q

What are the stages of atherosclerosis?

A

Edothelial dysfunction-progressive fatty streak-intermediate lesion- fibrous plaque/advanced lesion-plaque rupture

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63
Q

What is a fatty streak?

A

Earliest lesion in atherosclerosis, appear at very early stages less than 10years. Accumulation of lipid laden macrophages (foam cells) and T lymphocytes within the intimal layer of the vessel.

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64
Q

What is an intimediate lesion?

A

In intima layers of foam cells, vascular smooth muscle cells, pools of extracellular lipid/cholesterol (foam cells apoptose and release cholesterol crystals).
T-lymphocytes. Adhesion and aggregation of platelets to the vessel.
Still small asymptomatic lesion- most atherosclerosis stops here.

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65
Q

Why does most atherosclerosis stop at an intimediate lesion?

A

Protective mechanism.
Reverse cholesterol transport. HDLs contain apo-A1 particles to interact with foam cells to sequest cholesterol from them. Mature HDL then travels back to the liver to release the cholesterol (processed fro excretion). HDL particle then recirculate back to the heart and repeat the process.
ATHEROPROTECTIVE.

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66
Q

What are fibrous plaques/advanced lesions?

A

Thought to need another risk factor e.g. area of distubed flow etc to overcome the protective HDL mechanism.
Cytokine release by cells cause SMC proliferation and depositio of connective tissue. This leads to dense fibrous cap overlying a lipid-rich core (collagen=strength) (elastin=flexibility).
Lipid core beneath contains necrotic and apoptotic debris, SMCs, foam cells, T lymphocytes, macrophages.
This impedes blood flow as the plaque pushes out into the vessel lumen.

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67
Q

What causes the foam cells to apoptose? Causing?

A

The cholesterol crystals inside the foam cells- causing the release of these into the necrotic core. Further attracts macrophages to the area.

68
Q

What causes the plaque rupture of an atheroma?

A

PLaques constantly growing, and the fibrous cap has to be resorbed and redeposited to be maintained, but under inflammatory conditions the collagen can be broken down e.g. by increased matix metalloproteinases and gelinase- cap becomes weak.

69
Q

After plaque rupture?

A

AFter rupture T lymphocytes and macrophages upregulate the release of coagulants, promoting thrombus formation which can occlude the vessel. MI, stroke, death.

70
Q

small vs large necrotic core different ruptures?

A

LArge necrotic core: PLaque is torn leading to rupture

Small: Gradual erosion (less dangerous)

71
Q

How are small necrotic core and large thrombi different?

A

Small: Doesn’t rupture as such just erodes- White thrombus instead of red. No red blood cells, rich in proteoglycan, glycosaminoglycan. Platelet-rich. Little or no lipid core so occludes vessel less. Neutrophils here, and VSMCs.

Large: Ruptures, fibrin rich thrombus. Many macrophages. Large lipid core, thrombus occludes the vessel more, and focused at the rupture so can dislodge.

72
Q

Why are the small vs large necrotic cores ruptures different?

A

Large: Rupture: Type IV collagenases remove endothelial cells from the baselment membrane by lysis of the EXC Matrix. Endothelial cell death.
Small: Disturbed flow sloughs off the endothelial cells, exporsing the lower layers, where platelets can activate and adhere. Thrombus forms here.

73
Q

Why are lipids moved in liposomes?

A

Because they are hydrophobic.

74
Q

Diamerters of different lipoproteins?

A 
HDL: 7-20nm
LDL:20-30nm
VLDL: 30-80nm
Cylomicrons: 100-1000nm.
 (IDL also)
75
Q

Apoproteins of different lipoproteins?

A

HDL: ApoA 1 or 2 (gives apo-C and Es to chylomicrons and VLDLs to mature them)
LDL: ApoB 100
VLDL: ApoB-100
Cylomicrons: ApoB-48

76
Q

Three pathways for lipoproteins?

A

Exdogenous: lipids absorbed over the intestines (diet) combine with cylomicrons in blood.
Endogenous: Lipids metabolised taken from the liver into the blood.
Reverse: HDLs get lipids from tissues and taken to the liver for excretion.

77
Q

Exogenous pathway?

A
  1. Cholesterol/lipids are transported across the small intestine lumen through NPC1L1 transporter into lymphatic vessels.
  2. They are assembled with apo B-48 into nascent chylomicrons. To the LIVER and then to bloodstream.
  3. Chylomicron interacts with HDL which donates Apo-C and Apo-E- ACTIVE MATURE CHYLOMICRON.
  4. This activated tissue LPL (lipoprotein lipase) via ApoC.
  5. LPL in target tissue hydrolyses the chylomicrons into releasing glycerol and fatty acids (lipids), which is absorbed by the tissue (adipose tissue).
  6. The remnant chylomicron (with cholesterol) continue in circulation to the liver (ApoE and ApoB48 binds to receptors on the liver).
  7. cholesterol is stored in the liver, secreted in ble, oxidised to bile acids or converted into VLDL.
78
Q

Which apolipoproteins bind to what?

A

ApoC can only bind to receptors on adipose tissue (chylomicron), ApoE or ApoB48 binds to receptors on hepatocytes. (chylomicrons)
ApoB-100 to receptors on hepatocytes.

79
Q

Endogenous pathway?

A
  1. Liver synthesises cholesterol and triglycerides. These are assembled with apoplipoprotein B-100 to form a nascent VLDL.
  2. VLDL is released into the bloodstream, and interacts with HDL to recieve an apo-C-II and apoE= ACTIVE VLDL.
  3. VLDL travels in blood until reaches target tissue. ApoC-II activates LPL.
  4. LPL hydrolyses the VLDL and releases the fatty acids and glycerol which is absorbed by adipose tissue.
  5. The VLDL shrinks into an IDL. Some IDL is taken up by the liver (ApoE binding to LDLR) where hydrolysed to LDL, or some IDL remains in circulation to be converted to LDL.
  6. LDL binds to tissues via Apo C to release cholesterol or to LDLR on liver via ApoB 100 and sequest cholesterol.
80
Q

Reverse pathway?

A
  1. ApoA1 in HDL binds to transport proteins ABC-A1 or ABC-G1 in macrophages/foam cells and adsorb cholesterol.
  2. HDL then transports cholesterol to liver via either direct or Indirect pathway.
  3. Indirect pathway: cholesterol esters transfer to VLDL and LDL particles via cholesterl ester transport protein (CETP). Bind to LDL on LDLR on liver, or back to tissues updoing HDL’s good work.
  4. Direct pathway: ApoA1 of HDL binds to SRB1 receptor on liver. Cholesterol transferred to liver and HDL recirculates.
  5. Cholesterol in liver is either stored, secreted in bile, excreted.
81
Q

What is dyslipidaemia? Causes?

A

Abnormal lipid content in the blood, usually hyperlipidaemia (high).
Primary: Polygenetic or diet.
Secondary: Due to another problem e.g. uncontrolled diabetes, alcoholic, other drugs like isotretinoin- so treat these underlying causes.

82
Q

Frederickson classification for?

A

Dyslipidaemia when due to genetics e.g. Familial hypercholesterolaemia.

83
Q

What is familial hypercholesterolemia?

A

Genetic disorder causing v high LDL levels in the blood and early caridovascular disease.
Mutations in LDLR gene or Apoplipoprotein B- other mutations exist but are rare. Only 40% monogenic, mostly thought to be poly.

84
Q

Epidemilogy of FH?

A

+/- 1/500 people
Likely premature cardiovascular disease 30-40 and MI by 50.
-/- Atherosclerosis in childhood and CVD.

85
Q

FH treatments?

A

Little response, but PCSK9 inhibits have some benefit, but dialysis like treatment where drain blood, remove LDL and occasionally liver transplant.

86
Q

Drugs for dyslipidaemia?

A

Statins, Ezetimibe, Fibrates, bile acid sequesterants, PCSK9 inhibitors.

87
Q

How do statins work?

A

HMG- CoA reductase reversible competitive inhibitors. Rate limiting step of cholesterol synthesis, inhibit the enzyme that causes the conversion of HMG CoA into mevalonic acid, which is a cholesterol precursor.

If liver cant synthesis cholesterol it upregulates the LDL-Rs to sequest more from the blood stream.

88
Q

Statin examples?

A

Simvastatin, Lovastatin, Pravasatin- specific reversible competitive, short-acting. ORALLY
Rosuvastatin/Atorvastatin- long lasting inhibitors.

89
Q

Statins metabolism etc?

A

absorbed into the liver and metabolised by Cytochrome P450 enzymes which patients levles vary the half life (breakdown) of statins. Dose varies acording to patients enyme levels etc, may be best to give another statin type.

90
Q

Statins other impact on atherosclerosis?

A 
PLeiotropic effects: 
Other products of mevlonate pathway have atherogenic impacts. 
- decrease vascular inflammation. 
-Decrease platelet aggrability
-Neovascularisation of ischaemic tissue
-stabilise atherosclerotic plaques
antithrombotic actions
 BUT NOT USED IF PREGNANT as inhibts germ cell migration during development
91
Q

Statins side effects?

A

Muscle pain, GI distrubance, rasied conc of liver enzymes, rash, insomnia, skeletal muscle damage (rare, at high doses), 1% chance devloping diabetes- about same chance of getting MI/ stroke in low risk patients.
But same side effects with placebo?? But these industry funded studies- not all info available.

92
Q

Problem with people taking statins?

A

50% of patients stop taking after 1 year as see symptoms of drugs but no symptoms for their atherosclerosis.

93
Q

Fibrates for?

A

Atherosclerosis. Less used now- PCSK9 inhibitors replaced after statins and ezetimibe not tolerated.

94
Q

How do fibrates work?

A

Activates the PPAR alpha receptor which switches on genes for lipid metabolism.
These are Peroxisome proliferator-activated receptors- intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation. Activation induces genes that metabolise lipids e.g. LPL, apo A1 and Apo A2.
Decreases VLDL and therefore decreasing LDL levels by 10%, but increasing HDL by 10%.
ATHEROSCLEROSIS.

95
Q

Fibrates metabolism?

A

By CYP3A4- enzyme mainly in liver and intestines.

96
Q

Fibrates effectiveness?

A

Rarely used now, but can in treatment resistant dyslipidaemia. Decrease MI likelihood but no impact on survival.

97
Q

Fibrates side effects?

A

Mild stomach upset, myopathy (muscle pain) especially with statins- risk of kidney failure, One type=risk of gallstones (increases cholesterol in bile so only given to patients with gall bladder removed), Not to alcoholics-muscle inflammation

98
Q

Ezetimibe works how?

A

Atherosclerosis.

Inhibit the NPC1L1 transport protein in enteroscytes brush border, so inhibit the cholesterol absorption from the intestines. Not enough lipids to make a chylomicron so cant release into vessels.

99
Q

Ezetimibe advatnages/ disadvantages?

A
  • doesnt effect absorption of fat-soluble vitamins, triglycerides or bile acids).
  • Expensive. Given after statins.
    -Can enter milk so not when breastfeeding
    + High potency only 10mg/day reduces LDL cholesterol by 17-19%. Or with statins 25%.
    + Long half life, 22hours 1 pill a day.
    +Doesnt interact with other drugs.
100
Q

Ezetimibe side effects?

A

Mild diarrhoea, abdominal pain, headache, rash, angio-oedema (swelling of deep layers of the skin)

101
Q

Resins for? Examples?

A

Atherosclerosis. First cholesterol lowering drug to be used clinically- bile acid sequestering

102
Q

Resins work how?

A

Atherosclerosis.
Stop untake of bile acids into blood (sequester) into intestinal tract.
Liver compensates by increasing metabolism of endogenous cholesterol into bile acids- increase LDL-R expression, increase LDL clearance and decrease LDL in plasma.

103
Q

Resins side effects?

A

Significant hence not used now.
Bloating, constipation, diarrhoea, nausea, bulky unpalatable tablets, 1 hour after or 4-6 hrs before other meds (awkward to plan). interfer with absorption of vitamins, digoxin, diuretics, warfarin, theyroid hormones, beta blockers, CCBs.

104
Q

PCSK9 inibitors for? What are they?

A

Atherosclerosis.

monoclonal antibodies to inactivate PCSK9 enzyme e.g. Evolocumab or Repatha etc. IV injection.

105
Q

How do PCSK9 inhibitors work?

A

PCSK9 enzyme binds to LDL Rs on liver internalises and degrades them so there is a decrease in LDL uptake into the liver for sequestering. Higher LDL circulating. AB to PCSK9 so that it cannot then bind to the LDL-Rs to internalise them.
Subcutaneous injection 1 every month.

106
Q

Effectiveness of PCSK9 inhibitors?

A

Placebo+ statin- 2.8 cholesterol level
Ezetimibe +statin- 2.2
PCSK9 I +statin= 0.91

107
Q

PCSK9 inhibitors side effects?

A

Nasopharyngitis, influenza, back pain, injection site reactions, hypersensitivity reactions e.g. rash, eczema, erythema.

108
Q

Plant sterols use?

A

Atherosclerosis, and general lipid lowering. Put in yoghurts to ‘lower cholesterol’. Virtually unabsorbed by the body so stay in system a long time.

109
Q

Plant sterols how work?

A

Instead of the body taking up cholesterol across intestines, it takes up plant sterols into chylomicrons. Can reduce cholesterol by 40-45% but have to eat a lot.
Can also increase cholesterol excretion by actiating transport proteins like ABC G5/6 in enterocytes.

110
Q

Phases in drug development?

A
  1. Identify drug target.
  2. Design and optimise a drug
  3. Preclinical trials: Animals- efficacy? Toxicology?
  4. Phase 1: healthy volunteers, small group.
  5. Phase 2: small scale in target pop- safety? Tolerability? Efficacy?
  6. Large scale studies in target pop= safety efficacy.
111
Q

What is arterial thrombosis?

A

After atherosclerosis, thrombosis here. Occludes vessel- can be stable fixed stenosis (narrowing) or can completely block- ischaemia, MI, Stroke, death.

112
Q

Differernt regions within a thrombosis?

A

Fibrin rich regions, and RBC rich regions.

113
Q

Activation of platelets how?

A

By shape change, from smooth discoid to spiny and pseudopodia like. This increases the surface area and the possibility of cell-cell interactions and linking to other platelets to plug a wound.
Glycoprotein IIb/IIIa receptors on surface increaese.

114
Q

Glycoprotein IIb/IIIa relevence?

A

Upregulated as platelets are activated. Increases the receptor affinity for fibrinogen. Fibrinogen links receptors, binding platelts together (aggregation).

115
Q

What can be antagonised to reduce platelet coaggulation?

A

Glycoportein IIb/IIIa. IV e.g. abciximab, tirofiban etc.

Blocks the receptor.

116
Q

Problems with Gglycoprotein IIb/IIIa blocking?

A

-Increased risk of major excessive bleeding offsets their benefit.
-Narrow therapeutic window- not effective at low doses but at high dose too high bleeding.
- Evidence supports continuing use in highest risk patients undergoing PCI. (percutaneous coronary intervention).
NOT USED NOW MUCH.

117
Q

Aspirin use?

A

An effective, but relatively weak, anti-platelet drug to inhibit coagulation.

118
Q

Aspirins mode of action?

A

Arachidonic acid is formed from membrane phospholipids by Phsopholipase A2.
Arachidonic acid is converted to prostaglandin H2 by either Cyclooxygenase 1 or 2 (COX 1 or COX2).
Aspirin (acetyl salicilic acid) irreversibly acetylates serine residue on COX1 (prostaglandin synthase). Arachidonic acid enters pocket and converted into prostaglandin H normally, but acetylated cant bind. Pg-H2 converts to Tx A2 which activates platelets via surface receptors.

Non reversible so as long as platelet is replenished (7-10days).

119
Q

COX enzymes?

A

COX-1 -constitutively active (protects GI mucosa, platelet aggregation- activation role, renal function).
COX2- inducible, inflammation induces synthesis.

120
Q

Aspirin in clinical trial?

A

In heart attack survival patients (35 days after), streptokinase decreased deaths from 12% to 9.2%, aspirin decreased to 9.4%. Had an additive effect together, but streptokinase not used now due to increased risk of bleeding in brain.

121
Q

Aspirin resistance?

A

Rare- In some patients has limited effect on platelets. Normally v reliable, but can decrease response in v obese.

Trial 2006: 7 days 100mg/day.
96 patients- median reduction in Thromboxane B2 from 322pg/ul to 3pg/ul (reduction of 99%).
One patient- only reduced 59%. (compliance?) But did decrease when at 300mg.

122
Q

Aspirin drug interactions?

A

ibuprofen binds reversibly to COX1, which when taken with aspirin may impair its actions as this binds instead and then dissociates (24hrs)
Trial:
Thromboxane B2 inhibition was decreased by 50% with the use of ibuprofen before aspirin

123
Q

Why are COX2 inhibitors not used much?

A

They have increased cardiovascular risks associated with inhibition.

124
Q

Platelet purinergic receptor actions?

A

ADP to:
P2Y1- Gq-PLC-PKA and Ca= platelet aggregation, shape change
P2Y12-Gi alpha- inhibition of Adenylyl cylase so reduction of CAMP=Amplification of platelet aggregation, proagulant activity. B- PI3Kinase
ATP to:
P2X1 increases Ca in= platelet shape change, amplification of platelet activation

125
Q

ADP induces platelet …by…

A

prolonged aggregation. To P2Y1 or P2Y12. Activated glycoprotein IIb/IIIa fibriinogen cross linking.

126
Q

ADP that acts on platelets comes from?

A

When activated they release ADP from granules inside them. Positive feedback.
Thrombin acts on PAR1 and 4 receptors on platelets which leads to ADP release.

127
Q

Positive feedback mechanisms after platelet aggregation?

A

Activation causes increased thrombin release, which induces release ADP from granules inside the activated platelets (thrombin binds to PAR1/4)
Thrombin also causes coagulation by increased fibrin production (mesh that binds platelets together).

128
Q

What factors cause platelet activation?

A

Seratonin, collagen, thromboxane A2, Thrombin, ADP.

129
Q

PTY12 -/- mice?

A

Mean thrombus area deccreased in response to injury, and was transient not sustained thrombus formation.

130
Q

Clopidogrel is what?

A

Clopidogrel (anti-platelet drug).

Its a pro-drug, needs converting into the active form e.g. Cyp 450 in liver.

131
Q

Disadvanatges of clopidogrel?

A

Needs metabolising into its active form, but most is broken down earlier stages, small proportional actually converted to active form to block PTY12.

132
Q

Clopidogrel in trial?

A

CURE TRIAL:
Clopidogrel + aspirin vs aspirin alone.
Reduced CV death/ MI or Stroke MACE-from 11.4% to 9.3%.

133
Q

Clopidogrel and ADP response?

A

Reduced response, but very varied response, some patients convert a lot better than others. One patient- who had a stent, got a thrombosis on and had a MI.
Some patients convert better than others e.g. hae higher Cytochrome P enzyme levels.

134
Q

Clopidogrel drug interactions?

A

Omeprzole (a proton pump inhibitor) inhibits the conversion of clopidogrel to the active form.

Rifampicin for TB increased cytochrome enzyme levels so increases active metabolite levels. Increases the blockade of P2Y12, and platelet aggregation.

135
Q

Genetic LOF of CYP2C19?

A

30% people have. Low conversion of clopidogrel, stent thrombosis increased from 0.5% to 2% in 30 days.

136
Q

Personalisation of clopidogrel dose?

A

VerifyNow P2Y12 assay- test CYP levels in blood. Can predict clinical outcomes, and predict dose.
Also age, weight, diseases like diabetes, chronic kidney disease,, drug-drug interactions

137
Q

Prasugrel?

A

A more effective antiplatelet aggregation drug than clopidogrel? Although still a prodrug, esterases activate it instead of inactivating.
Active metabolite x60 more potent and prolonged time active.

138
Q

Trials on prasugrel?

A

Trial: Increased inhibtion of platelet aggregation in nearly all patients.
Trial on patients with stents- more than halved stent thrombosis compared to clopidogrel, but increased fatal bleeding.

139
Q

Drugs that block P2Y12?

A

Clopidogrel, Prasugrel, Ticagrelor

140
Q

Ticagrelor?

A

Binds reversibly to P2Y12- orally taken.

141
Q

Ticagrelor studies? (pre and II)

A

Pre-clinical: Increased inhibition of thrombus formation to the same extent as P2Y12 -/- mice.
Phase II: Faster drug onset, and larger response at lower dose, with same quicker recovery time after last dose (e.g. surgery), as reveribly binds not irreversibly like clopidogrel.

142
Q

Ticagrelor study (III)?

A

Ticagrelor vs clopidogrel:
T: MOre effective for reducing CV death. But causes more major bleeding. Long term decrease in fatal bleeding though as reversible.

143
Q

Ticagrelor analysis by NICE?

A

NICE agreed was cost effective.
Adopted in hospitals e.g. Sheffield one of the first. Decrease in in fatal bleeding, ST elevation when paired with aspirin. Decrease in ischaemic events. decreased deaths.

144
Q

Approprotiate vs non appropriate clotting?

A

Haemostasis (e.g. if cut) vs thrombosis in arteries or veins.

145
Q

How do platelets aggregate at a wound? (primary Haemostasis)

A
  1. Vessel wall exposes collagen.
  2. VWF binds to the collagen.
  3. Platelets bind to VWF via glycoprotein IIIa/IIb (integrein complex) receptors. (Initial adhesion)
  4. Platelets then bind to other receptors on the suface and activate other platelet receptors. (activation)
  5. Other platelets can then bind and aggregate with fibrinogen between their glycoprotein receptors. (aggregation) ADP and TxA2 released.
146
Q

Two platelet problems one can have?

A

NOt enough or don’t adhere to exposed collagen/ aggregate

147
Q

Most common cause of lack of platelet function? Fix?

A

Anti-thrombotic drugs or Von willebrand disease. Haemophilia.
PLatelet transfusion.

148
Q

Von willebrand disease?

A

VWF levels lower. Milder than haemophillia but bleeding heavily, e.g. v heavy periods etc.

149
Q

Von willebrand disease fix or other clotting disorders?

A

Primary Haemostasis: Desmopressin- stimulate body to produce VWF normally but not normally in circulation.
Add VWF concentrate-with CF 8. IV.
PLatelet transfusion (infection, dilute unpersonalised)

Secondary Haemostais: Specific factor concentrate.

150
Q

Secondary haemostasis coagulation cascade? Brief.

A
  1. Tissue factor exposed in injury- activates factor 7a (VIIa)
  2. Fibrinogen converted to fibrin by thrombin (mesh that supports clotting)
151
Q

Secondary haemostasis coagulation cascade? Long.

A
  1. Tissue factor exposed in injury- activates factor 7a (VIIa)
  2. 7a promotes the convertion of factor 9 (IX) into 9a.
  3. factor 9a, 7a and 8 promotes the convertion of 10 into 10a.
  4. 10a (Xa) activates factor 2 (II) which is converted into 2a (thrombin).
  5. Thrombin converts fibrinogen into fibrin which forms a mesh over platelets.
152
Q

Plaster analogy?

A

Plaster: Primary haemostasis- platelts plugging the hole.
Sticky part of plaster: VWF.
But not v strong- spray with superglue: Secondary haemostasis coagulation cascade fibrin mesh cover.

153
Q

Haemophilia deficiencies?

A

A- factor 8 deficiency
B-9 deficiency.
Others rare.
X linked- females only carriers. Bleed into joints muscles etc.
Classified according to percentage of WT have.

154
Q

How are clotting factors to give to patients got?

A

plasma derived or recombinat technology made. Put gene into cell line.

155
Q

Two different types of thrombosis? Differences?

A
  1. Arteriole- high pressure system, platelet rich (treatment inhibit platelets). MI, stroke.
  2. Venous- low pressure system (Problem with coagulation cascade- inhibit this). Deep Vein T, Pulomonary embolism.
156
Q

Antiplatelet drugs?

A

Aspirin, ticagrelor, clopidogrel, prasugrel,

157
Q

Anticoagulation drugs?

A

Heparin (Iv continous infusion or low molecular weight SC), Warfarin (oral), direct oral anticoagulants.

158
Q

Warfarin is what?

A

Anticoagulation drug: Vitamin K antagonist.

159
Q

Heparin mode of action?

A

Anti-thrombin naturally inhibits the coagulation cascade. Heparin (glycosaminoglycan) activates this. Also inhibits 9a and 10a,

160
Q

Heparin Low molecular weight pharmacokinetics?

A

SC, renally excreted once a day. Dose dependent on weight.

161
Q

Warfarin mode of action?

A

inhibits production of clotting factors 2, 7, 9, 10.
GGCX carboxylates the clotting factors to mature. GGCX needs vitamin K. The vitamin K gets oxidised and so needs to be reduced again by (Vitamin K reductase VKOR). Warfarin inhibits the VKOR.

162
Q

Warfarin measuring?

A

International normalised ratio- Normal 1 to 2 (2x as long for blood to clot). Dose depends upon- and need to emasure INR before surgery. Blood test every week to 8 weeks. Slow on and off (around 4 days for on and off)

163
Q

Warfarin dose depends upn?

A

Cyp2C9 (breaks down), VKOR (vitamin K reductase). Blood test, plot plymorphisms into online and tells doctors dose.

164
Q

Advantages of Direct oral anticoagulants?

A

Same dose, short onset and off. No drug, alcohol etc interactions. Orally taken. Half life around 5 hours.

165
Q

Direct oral anticoagulants mode of action?

A

One inhibits thrombin, others 10a (xa in name)

166
Q

Direct oral anticoagulants disadavantages?

A

More expensive than warfarin,
10a Not all got antidotes yet if need surgery licenced but is made soon will be. MAB for one that inhibits thrombin-liceneced.
recent introduction, so not as well tested as warfarin.

BMS 109 (20 decks)

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