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MPharm Y3S1 > CVD Pharmacology > Flashcards

CVD Pharmacology Flashcards

1
Q

Describe the function of the right side of the heart:

A

Right- deoxygenated
Right atria, blood is being received from vena cava
Right ventricle pumps deoxygenated blood to the lungs via pulmonary artery
Right side has tricuspid valve

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2
Q

Describe the function of the left side of the heart:

A

Left-oxygenated, receiving from lungs to the body
Left, blood is coming from the pulmonary vein
Left ventricles, oxygenated via aorta to the body
Left side has a thicker wall as more force
Left side has mitral valve

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3
Q

Name the 2 atrial ventrical valves:

A

Bicuspid (mitral)- left, 2 leaflets
Tricuspid- right, 3 leaflets

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4
Q

Describe the surround features of valves to aid them:

A

Valves are supported by chordae tendineae
Activated by papillary muscles which contact with ventricles to prevent back flow

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5
Q

Name and describe the 2 pulmonary and aortic valves:

A

Near the top
Arteries only (not veins)
3 cusps
Semi-lunar (half moon)
Eversion prevented by upturned nature and positioning of cusps
Close under back pressure

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6
Q

What is the brief definition of diastole?

A

Heart is relaxing and filling- isovolumetric ventricular relaxation

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7
Q

Describe diastole:

A

Beginning:
-all valves are closed- ventricles empty, atria starts to fill
Proceeds diastole:
-weight of blood eventually opens AV valves but aortic and pulmonary valves close, blood from atria to ventricles (ventricular filling)
End stage:
-AV valves open, atria contracts to push remaining blood into ventricles, aortic and pulmonary valves remain closed, blood is transferred to ventricles ready for pumping into arteries

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8
Q

What is the brief definition of systole?

A

Contraction and emptying of the heart- isometric ventricular contraction

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9
Q

Describe systole:

A

Beginning:
-all valves are closed- AV closed to prevent backward flow of blood from ventricles to atria
Then:
-ventricular ejection, blood flows out of ventricles so ventricles contract, AV valves close and aortic and pulmonary valves open, increasing pressure and decreasing volume

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10
Q

What is end systolic volume?

A

Amount of blood in ventricle at end of systole

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11
Q

What is end diastolic volume?

A

Amount of blood at end of diastole

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12
Q

How much blood has to be in the heart before an arterial contraction?

A

80% filled

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13
Q

What is the equation for stroke volume?

A

End diastolic volume- end systolic volume

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14
Q

What connects the myocytes (cells in the heart)?

A

Desmosome- mechanical support, cells are attached and can’t pull away from each other
Gap junctions- transmission of the A/P

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15
Q

Describe the pericardial sac and its function:

A

Double walled sac
Tough covering- anchors heart
Secretory lining- pericardial fluid, lubricaiton

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16
Q

What is pericarditis?

A

Painful rubbing
Viral/bacterial
Fluid becomes inflamed

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17
Q

What does autorhythmic mean in terms of the heart?

A

1% of regions of heart are auto rhythmic which means it can generate action potentials
99% contracts

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18
Q

Briefly describe the heart beat:

A

Simultaneous dual pump
Each beat triggers by depolarisation via an action potential

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19
Q

Name the regions of the heart which aid in the auto rhythmic section:

A

Sinoatrial (SA) node- pacemaker cells
AV node
Bundle of His
Purkinje fibres

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20
Q

Describe the electrical activity of the pacemaker cells:

A

No resting potential, the pacemaker potential is a relatively slow depolarisation
Funny channels- allow slow drift to happen, allow Na+ to enter, increase charge so depolarisation
As approaching threshold, transient (T type) Ca2+ channels open (more depolarisation)
At threshold Ca2+ channels close and long lasting (L type) Ca2+ ion channels open and rapid depolarisation
At peak the Ca2+ channels close and delayed rectifier K+ channels open letting K+ out, quick repolarisation
As soon as repolarised this process happens again

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21
Q

Where do cardiomyocytes pass the action potential?

A

From purkinje fibres to next cardiomyocyte

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22
Q

Describe the excitation A/P in contraction coupling in terms of calcium:

A

Increase in cytosolic calcium (in plateau phase)
From extracellular space
From sarcoplasmic reticulum
Combines with troponin- initiates cross bridge formation

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23
Q

Describe the second part of the excitation A/P in calcium contraction coupling:

A

Depolarisation of plasma membrane
Opening of plasma (L-type Ca2+ channels in T tubules)
Flow decrease of Ca2+ into cytosol
Ca2+ binds to Ca2+ receptors (Ryanodine receptor- RyR2) on the external surface of the sarcoplasmic reticulum
Opening of the Ca2+ channels intrinsic to these receptors
Flow of Ca2+ to the cytosol
Increase of cytosolic Ca2+ conc

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24
Q

How does Ca2+ re-enter the SR after depolarisation?

A

Ca sensitive receptors on SR (ryanodine receptor)
Active transport back into SR Ca2+ ATPase pumps (SERCA2a)
Na+/Ca2+ exchanger removes calcium from cytosol to the extracelluar space

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25
Q

What are the affects of abnormal levels of K+ on the resting potential?

A

Increase or decrease results in decrease cardiac excitability and contractility
Rise in extracellular K+ decreases resting potential (depolarisation)
Inactivates Na+ channels
Arrhythmias and fatalities
Decrease in extracellular K+ increases resting potential (hyper polarisation)
Bradycardia, cardiac rhythm abnormalities

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26
Q

What are the affects of abnormal Ca2+ levels on the resting potential?

A

Changes in the extracellular Ca2+ affects membrane permeability, which in turn causes cardiac rhythm abnormalities
Ca2+ blockers decrease force of contraction (inotropy)
Digoxin increases cytosolic Ca2+ and contractility

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27
Q

What is the cardiac refractory period?

A

Plateau phase- contractive response as Ca2+ joining in when Ca2+ out of cell, lose contractive response
Refractory period- cardiomyocytes can’t have another contractile response during peak/plateu

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28
Q

What is the P wave in an ECG?

A

Depolarisation of atria in response to SA node triggering AP (atria depolarisation)

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29
Q

What is the PR interval in an ECG?

A

Delay of AV node to allow filling of ventricles

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30
Q

What is the QRS complex in an ECG?

A

Depolarisation of ventricles, triggers main pumping contractions- main contraction of the heart

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31
Q

What is the ST segment in an ECG?

A

Beginning of ventricle repolarisation, should be flat

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32
Q

What is the T wave in an ECG?

A

Ventricular re-polarisation

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33
Q

What can an ECG be a diagnosis of?

A

Abnormalities in Rate
Abnormalities in Rhythm:
-atrial flutter
-atrial fibrillation
-ventricular fibrillation
-heart block
Cardiomyopathies
-ischemia
-infarct

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34
Q

How do you label a carboxylic acid?

A

Count from the carbon starting at the carboxylic acid
C18= 18 carbons
C180= no double bonds, saturated
C189= double bond at 9th carbon, count from bottom

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35
Q

What is oleic acid?

A

Omega 9
18C and double bond found at position 9

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36
Q

What is linoleic acid

A

Omega 6
Polyunsaturated FA
Double bond found on 6th carbon

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37
Q

What is a-Linolenic acid?

A

Omega 3
Polyunsaturated FA
Double bond found on 3rd carbon

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38
Q

Why do we need fats for?

A

Energy store- 1g=9kCal
Vitamins/antioxidants
Insulation
Protect organs e.g fat around kidneys
Structural e.g brain
Phospholipids- cell membrane integrity
Hormones-PGs
Gene expression
Essential FA

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39
Q

How is fat digested and absorbed?

A

Diet (large triglyceride droplets)
Emulsified in intestine by bile salts (detergent)
Smaller lipid particles, to increase SA for enzyme, pancreatic lipase
Monoglycerides and free FA (water insoluble)
Bile salts facilitates the transport of these to epithelial cells of SI via micelles from lumen by diffusion
Then reform into triglycerides
Aggregate and form proteins and lypoprotein then into chylomicrons to lymphatic vessel and lacteal cells into blood

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40
Q

How are lipoproteins transported?

A

Lipids and cholesterol transported in blood as complexes of lipids and protein called lipoproteins
Hydrophobic core of lipid (triglycerides and cholesterol esters)
Hydrophilic coat of polar phospholipid, free cholesterol, and apoprotein

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41
Q

What is the density like of lipoproteins with more/less lipid and cholesterol?

A

Lipoproteins with more proteins are generally more dense as proteins are heavier than lipids
Lipoproteins with more lipids are lower density

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42
Q

What are apoproteins?

A

Act as ligand on different receptors on body, helps uptake of lipoprotein, depends on type of apoprotein as to where its taken up

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43
Q

Name the 5 classes of lipoproteins:

A

Chylomicrons- fat absorption from intestine
Very low density lipoproteins (VLDL)
Low density lipoproteins (LDL) -bad
Intermediate density lipoproteins (IDL)
High density lipoproteins (HDL) -good

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44
Q

Describe chylomicrons:

A

Main component is triglycerides
Diameter 75-1200 (largest)
Density less 0.95 (lowest density)
Apoprotein B48 (A,C,E)- allows interaction with peripheral cells in the liver

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45
Q

Describe VLDL:

A

Main component TG
Diameter 30-80µm
Density 0.95-1.006
Apoproteins B100 (A,C,E)

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46
Q

Describe IDL:

A

Have a mix of both TG and cholesterol
Diameter 25-31
Density 1.006-1.019
Apoproteins B100 (E)

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47
Q

Describe LDL:

A

Main component is cholesterol
Diameter 18-25
Density 1.019-1.063
Apoproteins B100
Bad as can leave behind cholesterol deposits

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48
Q

Describe HDL:

A

Main components are protein
Diameter 5-12 (smallest)
Density 1.063-1.210 (highest density)
Apoproteins A1,A2, (C,E)
Good as it assists in a process called reverse cholesterol transport

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49
Q

Describe the pathway for exogenous lipids:

A

Cholesterol and TG from the diet are absorbed in the ileum transports in the chylomicrons to the lymph, blood then capillaries to the muscle and adipose tissue
TG is hydrolysed by lipoprotein lipase to glycerol and free FAs, which are taken up into tissues
Remaining chylomicrons remnant with cholesteryl esters and travel to the liver, bind to LDL receptors and are endocytose
Cholesterol is stored, oxidised to bile acids or enters the endogenous pathway

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50
Q

Describe the pathways for endogenous lipids using LDLs:

A

Cholesterol (15% from the diet and 85% newly synthesised in the liver) and newly synthesised TG travels as VLDL to muscle and adipose tissue
TG is hydrolysed in tissue by lipoprotein lipase to glycerol and FFA liberated
Lipoprotein particles become smaller but retain cholesteryl esters and become LDL, which binds to LDLr on cells (LDLr recognise apoB100 on LDL particles)
Cholesterol deposited in tissues for cell membranes and other functions

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51
Q

Describe the pathways for endogenous lipids using HDLs:

A

Cholesterol can return to plasma and liver from tissues via HDL (reverse cholesterol transport)
Cholesterol esterified with long chain FA in HDL and transferred to VLDL or LDL in plasma by cholesteryl ester transfer protein (CETP)

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52
Q

What drugs can work on the exogenous lipid pathway and how?

A

Ezetimibe decreases absorption of cholesterol from going to chylomicrons

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53
Q

What drugs can work on the endogenous lipid pathway and how?

A

Statins, resins and fibrates increase re-uptake of LDL into coated pits of hepatocytes
Statins also decrease synthesis of cholesterol

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54
Q

What is the function of ApoB48?

A

In chylomicrons, essential for intestinal absorption of dietary lipids

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55
Q

What is the function of ApoE?

A

In chylomicrons, mediates uptake of chylomicron remnants into liver by LDL receptor

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56
Q

What is the function of ApoB100?

A

In VLDL, LDL and LDL, main physiological ligand for LDLr and synthesised in the liver

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57
Q

What is the function of ApoA1?

A

In HDL, promotes cholesterol efflux from tissues to liver for excretion

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58
Q

Where are LDL receptors found?

A

On all nucleated cells
Increased expression on hepatocytes

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59
Q

Describe the joint stage in the LDL receptor pathway:

A

LDL lipoproteins binds to the LDLr on hepatocytes causing receptor mediated endocytosis
The LDLr is taken up to a coated vesicle, drop in pH from 7 to 5 which causes LDL to dissociate from the receptor
Vesicle then pinches to form 2 smaller vesicles:
-One free LDL
-Receptor of LDL

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60
Q

Describe the LDL receptor pathway for the free LDL vesicle:

A

Free LDL vesicle fuses with lysosome which causes release of cholesterol from cytosol
So it can then help:
-membranes
-steroid hormones
-bile acids, lipoproteins
-regulatory actions

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61
Q

Describe the LDL receptor pathway for the LDLr vesicle:

A

Recycling vesicle fuses with cell membrane, turns it inside out, exocytosis of LDLr are returned to cell surface so can happen the LDL receptor pathway can happen again

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62
Q

Describe Reverse Cholesterol Transport:

A

Net movement of cholesterol from peripheral tissues back to liver, so not deposited in cells that don’t need it
Pre-beta HDL- very protein rich disc shape particles (not mature yet)
LCAT esterifies- cholesterol from peripheral cells and HDL molecules become spherical
Cholesterol esters transferred by CETP
Returns back to liver and can be excreted

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63
Q

Name the lipid transfer proteins involved in lipid transport:

A

ACAT- acetyl CoA- cholesterol acyltransferase
LCAT- lecithin cholesterol acyltransferase
CETP- cholesterol ester transfer protein
PLTP- phospholipid transfer protein

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64
Q

What is the function of ACAT?

A

Catalyses intracellular synthesis of cholesteryl ester in macrophages, adrenal cortex, gut and liver
Tamoxifen is a potent ACAT inhibitor

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65
Q

What is the function of LCAT?

A

Catalyses cholestryl ester synthesis in HDL particles

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66
Q

What is the function of CETP?

A

Transfer of cholestryl ester between HDL to IDL or VLDL

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67
Q

What is the function of PLTP?

A

Transfer of cholesterol and TG between different classes of lipoprotein particles in plasma
CETP inhibition is a potential therapeutic strategy

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68
Q

What is dyslipidemia?

A

Disorder of lipid metabolism including lipoprotein overproduction and deficiency

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69
Q

What can be the causes of dyslipidemia?

A

Increase in total cholesterol (TC)
Increase in LDL (increase deposited in arteries)
Increase in triglyceride
Decrease in HDL

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70
Q

Describe the first stage of atherosclerosis:

A

Form of injury e.g smokers, diabetes
-endothelial permeability
-leukocyte migration
-endothelial adhesion
-leukocyte adhesion

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71
Q

Describe the second stage of atherosclerosis:

A

Foam cell formation- stick down under endothelial layer
Plaque formation
-smooth muscle migration
-adherence and aggregation of platelets
-adherence and entry of leukocytes
-T cell activation

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72
Q

Describe the third stage of atherosclerosis:

A

Plaque gets bigger
-Macrophage accumulation
-formation of necrotic core- blood isn’t reaching cells
-fibrous cap formation

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73
Q

Describe the fourth stage of atherosclerosis:

A

Fibrous cap thins and plaque rupture
Haemorrhage from plaque micro vessels leads to a HA or stroke

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74
Q

How much LDL is part of TC and what is its main function?

A

60-70% of TC
Oxidised and deposited in BVs, leads to atherosclerosis

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75
Q

How much HDL is part of TC and what is its main function?

A

20-30% of TC
Transports excess cholesterol from peripheral tissues to liver
Antioxidant- decreases adverse effects from LDL

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76
Q

What is the epidemiology of dyslipidemia?

A

UK population has one of the highest rates
-60% of adults in england have TC>5mmol/L
Average TC in Middle Ages men and women between 5-6
Increase as you get older
Western diet leads to high TC
South asian population- higher % of population with HDL<1mmol/L e.g 20% Pakistani men have low HDL

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77
Q

Describe the aetiology of primary dyslipidemia:

A

60% have primary
Combination of diet and genetics
Genetics-5 inherited conditions
Diet and lifestyle

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78
Q

What are the diet and lifestyle factors which cause primary dyslipidemia?

A

High saturated fat
Smoking
Physically inactive
Overweight/obese
Large waist circumference

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79
Q

Describe the aetiology of secondary dyslipidemia:

A

40% have secondary
Underlying cause:
Disease or certain drug e.g thiazides, diabetes, liver disease, GC
Natural rise as age and after menopause

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80
Q

Name and describe inherited conditions that increase blood lipids:

A

Familial hypercholesterolaemia
-inherited higher levels from birth
-average 1 person/day has FH has a HA
Mutations in LDLr of ApoB OR PCSK9
Homozygous- rare 1/250000 >20mmol/L
Heterozygous- 1/250, CHD 20 years before general population if untreated, around 8mmol/L

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81
Q

Name different types of primary dyslipidemia:

A

Familial combined hyperlipidemia
Type 3 hyperlipidaemia
Polygenic hypercholestrolaemia
Primary hypertriglyceridaemia
Lysosomal acid lipase deficiency

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82
Q

Describe familial combined hyperlipidemia:

A

Inherited 1/100 in UK population
Increase cholesterol and triglyceride- raised by age 20-30
Raises VLDL and more compact and dense LDL than normal
Fasting TF> 1.5mmol/L

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83
Q

Describe type 3 hyperlipidaemia:

A

Inherited 1/5000-1/10000
High cholesterol and triglyceride
Mutations of ApoE

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84
Q

Describe polygenic hypercholesterolaemia:

A

More than 1 gene with changes
>12 genes linked to high cholesterol

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85
Q

Describe primary hypertriglyceridaemia:

A

Lipoprotein lipase deficiency
Affects 1 in a million
Very high triglyceride

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86
Q

Describe lysosomal acid lipase deficiency:

A

Breaks down fat into lysosomes normally but instead, fat builds up
Rare condition affects less than 1 in a million in UK

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87
Q

Name and describe the eyeball sign of hyperlipidaemia:

A

Corneal arcus
Cholesterol deposition around outer eye- grey ring on iris

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88
Q

Name and describe the skin signs of hyperlipdaemia:

A

Tendon xanthomas- raised areas on skin (elbows)
Xanthelsma- patches around eyes where cholesterol deposited

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89
Q

What underlying disorders can cause secondary dyslipidaemia?

A

Diabetes
Hypothyroidism
Chronic renal failure
Alcoholism
Liver disease

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90
Q

What drugs can cause secondary dyslipdaemia?

A

Thiazide diuretics
Loop diuretics
B blockers
Oral contraceptives
Ciclosporin
GCs
Isotretinoin
Tamoxifen
Protease inhibitors of HIV

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91
Q

Describe how lipoprotein (a) is a risk factor for thrombosis:

A

Apo(a) structurally similar to plasminogen
LP(a) inhibits binding of plasminogen to receptors on endothelial cells-leads to less plasmin (to break down clot) generation and promotion of thrombosis

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92
Q

What are the non-pharmacological treatment of dyslipidaemia?

A

Dietary modifications
-low salt fat, trans fat
-high mono or polyunsaturated fat to decrease LDL and increase HDL
-oily fish twice a week
-plants sterols and stanols to decrease cholesterol absorption from gut
-high fibre (soluble fibre) may decrease cholesterol absorption deem gut
-weight loss BMI< 25
-smoking
-physical activity, 30mins 5x week
-decrease alcohol

93
Q

Name the segments of the endothelial:

A

Inner most endothelial-detect blood flow
Middle smooth muscle cells and elastic components- BP
Outer- apprenticial layer

94
Q

Describe the process for atherosclerosis:

A

As we age, endothelial layers become damaged so endothelial cells become leaky, LDL can now pass, so sits on basement membrane of endothelial where becomes oxidised, so endothelial cells trigger markers for immune cells due to endothelial dysfunction
Immune cells can pass into basement membrane and destroy LDL but also other cells
Macrophages turn into foam cells so cause SM cells to migrate and proliferate, forming a fibrous cap to stop the blood being exposed to the necrotic plaque (stable plaque)
Overtime the cap will start to thin (unstable plaque) which can rupture, exposing the blood to the cell debris, causing a cascade of events which will eventually block the BVs because of clotting leading to HA/stroke

95
Q

What is hemostasis?

A

Arrest of blood loss from damaged BVs

96
Q

Describe the stages in hemostasis:

A

Wound
Vasoconstriction
Platelet activation and adhesion-> thrombosis
Formation of haemostatic plug (coagulation)
Fibrinolysis

97
Q

What is thrombosis?

A

Pathological formation of clot in vasculature in the absence of bleeding

98
Q

What can drugs target to affect haemostats and thrombosis?

A

Platelet adhesion and activation
Blood coagulation (fibrin formation)
Fibrin removal (fibrinolysis)

99
Q

What conditions are used for haemostasis promotion?

A

Haemophilia
Extensive anticoagulation therapy
Haemorrhage after surgery
Menorrhagia

100
Q

Describe the function of platelets:

A

Maintain integrity of circulation
Essential for haemostasis, healing of vessels and inflammation, formation of thrombi, first step in clotting cascade

101
Q

Describe the properties of platelets:

A

Adhesion following vascular damage
Shape change
Secretion of granule contents
Biosynthesis of PAF and PGs
Aggregation
Exposure of acidic phospholipid on surface

102
Q

When are platelets active?

A

Not normally active
Activated when exposed to damage

103
Q

What components of the extracellular matrix can activate platelets?

A

Von Willebrand factor (wWf)
Collagen
Platelets have receptors for these

104
Q

What soluble factors do platelets have receptors for?

A

ThromboxaneA2
ADP

105
Q

How can platelet aggregation lead to further activation?

A

aIIbB3 receptors bind to fibrin, which will form links between the platelets causing aggregation leading to activation
Change in shape due to cytoskeletal changes
They can contract leading to a concentration effect and further blocking

106
Q

What are factors that prevent/limit the activation of platelets?

A

NO, PGI2- both made by endothelial cells of the blood
Enzymes (CD39) which remove ADP to AMP

107
Q

What are ways of inhibiting platelet aggregation/activation?

A

Target factors that promote it- TXA2, ADP
Block binding of wWF or collagen
Can also stimulate the inhibitors of platelet aggregation:
-stimulate NO activation (short lived)
-increase PGI2 formation
-increase removal of ADP

108
Q

What are factors that activate platelets?

A

ADP binding
TXA2
Fibrinogen (GP IIb/IIIa)

109
Q

Name different classes of anti platelet drug:

A

Aspirin
Thienopyridines-clopidogrel, prasugrel
Ticagrelol
Glycoprotein IIb/IIIa inhibitors:
-eptifibatide
-tirofiban
-abciximab

110
Q

What are the different functions in terms of COX 1 and 2 for platelets?

A

COX 1 in platelet for TXA2 production
COX 2- platelet aggregation inhibitor, PGI2

111
Q

Why does aspirin work as an anti platelet even though it inhibits PGI2?

A

Endothelial cells can synthesise new COX2 so new PGI2
Platelets can’t because no nuclei, so no TXA2
Lower doses must inhibit platelets
Higher doses inhibit platelets and endothelial cells

112
Q

How do thienopyridines work?

A

Pro drugs, additive effect to aspirin because work on separate pathway
Inhibit ADP-induced aggregation (ADPr antagonists)
Antagonises the platelet P2Y12r (purinergic r) which will bind ADP

113
Q

How does Ticagrelor work?

A

Nucleoside analogue- like adenosine
Blocks P2Y12 ADPr on platelets
Different binding site than ADP so allosteric inhibitor and blockage reversible therefore acts faster and for shorter period

114
Q

Describe the advantages of Ticagrelor:

A

PLATO trial- ticagrelor less mortality from all CV causes than clopidogrel
Sts-more non lethal bleeding but effects more quickly reversible though

115
Q

How does the Glycoprotein IIB/IIIa receptor normally work?

A

Resting platelet- GP IIb/IIIa r in ligand unreceptive state
Agonist (ADP, thrombin etc) binds so activated platelet
GP IIb/IIIa r in ligand receptive state so fibrinogen binds to form aggregative platelets normally

116
Q

How do GP IIb/IIa receptor antagonists work?

A

Inhibition of platelet aggregation as occupying binding sites
Inhibit all pathways of platelet activation because bind to GP IIb/IIIa r blocking fibrinogen binding so inhibiting aggregation

117
Q

Describe the stages in coagulation:

A

Stage 1- platelets attaches to endothelial wall
Stage 2- platelets start to release fibrin and seal endothelium
Stage 3- the fibrin network traps the RBC and completely seals

118
Q

What is coagulation?

A

Formation of a fibrin clot or thrombus
Reinforces platelet plug
May trap BCs
-white thrombus -red thrombus

119
Q

Name and describe the 2 types of coagulation cascades:

A

Intrinsic or contact pathway e.g glass- all components present in blood
Extrinsic or in vivo pathway e.g tissue damage to realise tissue factor- some components from outside blood come in

120
Q

Describe the coagulation cascade for both intrinsic and extrinsic cascade:

A

Both converge at factor 10->10A
Asclerosis- thrombi formation extrinsic pathway
10A-> prothrombin-> thrombin which cleaves soluble fibrinogen to insoluble fibrin forming polymers which causes blood clot

121
Q

How is the platelet plug formed?

A

Platelet aggregation and activation interact with the coagulation cascade at different levels
Exposure of acidic phospholipids to outside of cell on platelets upon activation-> switches on the coagulation cascade which switches on the extrinsic pathway
The coagulation pathway can feed back to form platelet aggregation, factors which do this is thrombin, presence of fibrinogen

122
Q

Describe the role of thrombin:

A

Thrombin cleaves fibrinogen, producing fragments that polymerise to form insoluble fibrin
Activated factor XIII- strengthens fibrin links so further platelet aggregation
Cell proliferation
Regulates smooth muscle contraction

123
Q

What are the roles of the liver?

A

Synthesises clotting factor
Vit K (phytomenadione):
Synthesis of bile salts- vit K reabsorption

124
Q

What are the roles of vitamin K?

A

-‘koagulation’ vitamin
-lipid soluble
-required for synthesis of factors II,VII,IX,X
-dietary source
-synthesis of vit K in GIT

125
Q

What are the main drugs to treat platelet rich white thrombi?

A

Antiplatelet drugs- aspirin

126
Q

What are the main drugs to treat platelet rich red thrombi?

A

Injectable anticoagulants (heparin and newer thrombin inhibitors)- act immediately
Oral anticoagulants- (warfarin and related compounds)- takes several days
Pts with venous thrombosis given injectable anticoagulants until effects of warfarin established

127
Q

Why does warfarin have to be monitored so closely?

A

Warfarin can inhibit factor 9 and 10 and prothrombin and also factor 7 of the extrinsic pathway- lots of factors

128
Q

Where are heparins found?

A

Extracted from the liver, present in mast cells

129
Q

Describe the MoA of heparins:

A

Activates antithrombin III (ATIII)
-inactivates thrombin and factor 10a and other serine proteases
-binding changes conformation of ATIII
-accelerates rate of action of ATIII
Inhibiting a single molecule of 10a helps prevent the formation of hundreds of thrombin molecules

130
Q

Describe the structure of heparin:

A

Highly acidic sulphate groups- administered as heparin sodium

131
Q

What is the family of heparins?

A

GAGs (mucopolysaccharides)

132
Q

Name the 2 different compounds of heparin:

A

Unfractionated (UFH)-combo of all heparins
Low molecular weight heparins (LMWH)-purified

133
Q

Which one of the heparin compounds are more predictable and why?

A

UFH inhibits both thrombin and factor 10a, however the LMWH inhibits mainly factor 10a and therefore its affects more predictable
UFH in hospitals only because of this

134
Q

Describe the pharmacokinetics of heparin:

A

Not orally absorbed
-large size
-degradation
Partially metabolised in the liver by heparinise to uroheparin
-20-50% excreted unchanged
Parenteral admin
-IV or SC
t1/2 40-90 mins- acts immediately

135
Q

What are the advantages of using LMWH of UFH?

A

LMWH binds to less endothelium and plasma proteins hence have higher bioavailability and plasma half life than UFH
Predictable dose response (only affects Xa)- lab monitoring is rarely required
Reduced frequency of dosing
Less SEs
Can be used at home- convenience/ cost

136
Q

State how warfarin works:

A

Inhibits vit K reductase
Competitive inhibition

137
Q

What are the effects of vitamin K inhibition?

A

Inhibits hepatic vitamin K dependant synthesis of factors II,VII,IX and X and of anticoagulation protein C and its cofactor proteins

138
Q

What are the disadvantages of using warfarin?

A

Since warfarin acts indirectly, it has no effect on existing clots
Takes at least 48-72 hours to achieve an antithrombolytic effect as works on the level of transcription/protein synthesis and have to wait for the levels of the factors to decline

139
Q

Describe the pharmacokinetics of warfarin:

A

Readily absorbed through GIT
-quite lipophilic, in placenta and breast milk
Extensively bound to plasma proteins (99%)
Plasma half life of around 37hrs- variable
Metabolised by CyP450
Drug difficult to control due to these factors

140
Q

Describe the outline fibrinolytic system:

A

When homeostasis has been restored
Clot removal
-fibrinolytic pathway
-plasmin formation/activation
-potent proteolytic enzyme (attacks fibrin at 50 different sites)

141
Q

How is plasmin formed and activated?

A

Plasmin is formed by plasminogen C pro enzyme
Has affinity for fibrin but must be activated:
-tissue plasmin activators (tPA)
-urokinase plasminogen activator (UPA)
-kallikrein
-neutrophil elastase
Bottom 3 released from endothelium

142
Q

Describe the details/process of the fibrinolytic system:

A

Plasmin can bind to fibrin but won’t cleave it until activated
Plasmin is coming from blood (circulation) and then binds to the clot
The activation is balanced by inhibitors

143
Q

Describe the inhibitors of the fibrinolytic system:

A

Plasmin can be inhibited by a2 antiplasmin (in circulation) to form a2-antiplasmin/plasmin complexes
There are plasmin activator inhibitors (PAI) which are also released from endothelial cells

144
Q

Name the drugs that stimulate fibrinolysis and how?

A

They can convert plasminogen to plasmin:
-streptokinase
-Recombinant human tPA
–reteplase and tenecteplase
–alteplase
-Urokinase

145
Q

Describe the features of streptokinase:

A

Purified form streptococci
Cleared by the liver
Antigenic antibodies from 4 days after
Half life 20 minutes
Can’t be used for a year after one dose given due to reaction

146
Q

Describe the features of Altepase:

A

Decrease mortality in MI
Treatment of acute ischemic stroke, DVT an PE
More active on fibrin bound plasminogen than plasma plasminogen, therefore ‘clot selective’
Not antigenic
Given IV, half life 5 mins
Given within 6-12 hours , ideally within an hour

147
Q

Describe the features of reteplase and tenecteplase:

A

Decrease mortality in MI
More active on fibrin bound plasminogen than plasma plasminogen therefore ‘clot selective’
Not antigenic
Reteplase given within 12 hours , ideally less than 1 hr
Tenecteplase given within 6 hours, ideally less than 1 hour

148
Q

Describe the features of urokinase:

A

uPA
not selective for clot bound fibrin so less useful

149
Q

What is angina pectoris?

A

Tight chest
Symptom of a disease which is probably atherosclerosis
When oxygen supply to myocardium is insufficient for its needs

150
Q

Describe the symptoms of angina:

A

Retrosternal cardiac pain
-intense, diffuse, gripping, constricting, suffocating chest pain
-bear hug
-may radiate to arms, neck and jaw
-difficult to distinguish from heart burn

151
Q

What is atherosclerosis?

A

Block BVs that supply heart
Coronary arteries surround heart-cardiomyocytes sensitive to blood flow
Atherosclerosis will cause coronary artery to get smaller and plaque eventually raptures leading to clotting forming a thrombus

152
Q

What are the aims of treatment for angina/ atherosclerosis?

A

Alleviate acute symptoms
Minimise frequency of ischaemia
Decrease progression of atherosclerosis (2º prevention e.g statins, aspirin ACEi etc)

153
Q

What are the triggers for angina?

A

Cardiomyocytes and coronary arteries normally balance O2 needs vs supply
O2 needs- increase cardiac workload e.g excerise, emotion, GI perforation, peripheral vasoconstriction
O2 supply- restricted coronary perfusion e.g narrowing of coronary arteries (atheroma), limits on dilation, aortic stenosis

154
Q

What are ways to reduce oxygen demand?

A

Reduce cardiac workload
Reduce cardiac rate/contractility
Increase efficiency of the heart

155
Q

How would you reduce cardiac workload?

A

Decrease perfusion demands:
-e.g rest, stress, smoking, weight
Decrease preload:
-venodilator e.g nitrates
Decrease afterload:
-arterial dilatory e.g CCBs, nitrates

156
Q

How would you reduce cardiac rate/contractility?

A

Veinotrope/ chronotrope e.g B blocker, CCB

157
Q

How would you increase the efficiency of the heart?

A

Exercise
Stop smoking

158
Q

What are ways to improve oxygen supply?

A

Increase coronary flow
-arterial dilator e.g CCB, nitrate
-surgery e.g bypass, angioplasty, stent

159
Q

Name anti-anginal agents:

A

*Organic nitrates- acute attacks, mimic NO
*CCBs
*B adrenoreceptor antagonists- slow HR
Potassium channel activators
-vasodilators

160
Q

Name and describe examples of organic nitrates:

A

Glycerol trinitrate:
-explosive
-effective in angina
-quick onset, short DoA
Isosorbide mononitrate
-longer DoA

161
Q

Describe how nitrates work, at lower doses:

A

NO (donors), released from organic nitrates
Relaxes all SM
Main effects on CV system
Lower doses:
-marked dilation on large veins
-decrease in central venous pressure (decrease preload)
-decrease in CO and O2 consumption
-little effect on arterioles/ little change in BP

162
Q

What do nitrates cause at higher doses?

A

Not ideal
Arteriolar dilation, fall in BP, reduced CO, headache

163
Q

How is NO produced normally as a vasodilator?

A

Endothelial cells will recognise shear stress releasing NO
NO diffuses across membranes into SM cells leading to vascular relaxation

164
Q

How does NO cause vascular relaxation?

A

Guanylyl cyclase
GTP->cGMP->activation of cGMP dependent protein kinases-> dephosphorylation of myosin light chain via myosin light chain phosphotase
Leads to vasodilation, decrease preload, decrease workload and decrease O2 consumption of the heart

165
Q

Describe the effects of nitrates on coronary circulation:

A

Increase coronary flow in normal subjects
-decrease of vascular resistance
Dilation of coronary arteries despite a fall in BP
Diverts blood from normal to ischaemic areas

166
Q

Describe the pharmacokinetics of nitrates:

A

Glycerol trinitrate (nitroglycerin)
-absorbed sublingually (under tongue) rapid relief
-rabidly metabolised in liver (30 mins activity)
-can’t be swallowed (1st pass effect)
Sprays
Tabs- glass bottles as volatile
Patches

167
Q

How do B blockers work for angina?

A

Decreases oxygen consumption only
Depress the myocardium (-ve inotropy)

168
Q

How do B blockers decrease O2 consumption only?

A

Slows the heart (-ve chronotropy)

169
Q

How do B blockers depress the myocardium?

A

No effect on coronary arteries
Provide 2º prevention
Increase exercise capacity
CI in coronary spasm
Slow withdrawal (up regulate receptors)

170
Q

What are the indications of B blockers for angina?

A

Angina prophylaxis
Unstable angina

171
Q

What are the 3 main classes of CCBs and name a few:

A

Phenylalkylamines e.g verapamil
Dihydropyridines e.g nifedipines, amlodipine
Benzothiazepines e.g diltiazem

172
Q

How do CCBs work?

A

Block Ca2+ ions entering cells through preventing opening of voltage gated L type Ca channels so inhibition Ca entry caused by depolarisation in these tissues
Bind a1 subunit of the cardiac and also SM L type Ca channels but at different sites

173
Q

Describe where the different classes of CCBs can work:

A

Verapamil is relatively cardioselective
Nifedipine is relatively sm selective
Diltiazem is intermediate

174
Q

Describe the cardiac actions of CCBs:

A

Antidysrhythmic effects (mainly atrial tachycardia) because of impaired atrioventricular conduction
-decrease contractility
-negative inotropic and chrontropic effect (but little effect on CO due to decrease in peripheral resistance)
-verapamil CI in HF

175
Q

Describe the vascular SM actions of CCBs:

A

Mainly nifedipine
Arteriolar dilation, decreases BP, decreasing afterload
Coronary vasodilation- used in patients with variant angina (spasm)

176
Q

What is a cardia arrhythmia?

A

An arrhythmia is a problem with the rate or rhythm of the heart beat
During an arrhythmia, the heart can beat too fast, too slow or with an irregular rhythm

177
Q

Describe the Vaughan Williams classification:

A

Drug classification:
IA (moderate)
IB (weak)
IC (strong)
II
III
IV

178
Q

What drugs will work on class 1 of Vaughan Williams classification?

A

Na+ channel blockers, depends on how they affect A/P
IA- procainamide, quinidine
IB- lidocaine, phenytoin
IC- flecainide, propafenone

179
Q

Describe the function of class 1 drugs in the Vaughan Williams classification:

A

Block entry of Na+ ions in cardiomyocytes, still reaches peak
IA- reduce rate of raise of phase 0, lengthens A/P
IB- reduce rate of rise of phase 0, shortens A/P
IC- reduce rate of rise of phase 0, no effect on duration of A/P

180
Q

What drugs will work on class 2 of Vaughan Williams classification?

A

B adrenoreceptor blockers
Propranolol, metoprolol

181
Q

Describe the function of class 2 drugs in the Vaughan Williams classification:

A

Less A/P in a time
Predominant action on sinus node, decrease rate of slow drift, extend phase
-decrease myocardial infarction mortality
-prevent recurrence of tachyarrythmias
Propranolol also shows some class 1 action

182
Q

What drugs will work on class 3 of Vaughan Williams classification?

A

K+ channel blocker:
Amiodarone (has class I,II,III,IV activity)
Sotalol (also a Bblocker)
Ibutilide

183
Q

Describe the function of class 3 drugs in the Vaughan Williams classification:

A

K+ needed for repolarisation as pumped out of cardiomocytes via rectifier channels
Widen duration of A/P
Used in Wolff Parkinson-white syndrome
Sotalol- ventricular tachycardias and AF
Ibutlide- atrial flutter and AF

184
Q

What drugs will work on class 4 of Vaughan Williams classification?

A

CCBs
verapamil, diltiazem

185
Q

Describe the function of class 4 drugs in the Vaughan Williams classification:

A

Blocks Ca2+ on caridomyocytes
Predominant action on AV node- slowing transmission of AV node
Affect cardiomyocyte contraction (decrease Ca2+ entry) therefore the force of contraction decreases
Slow channel blockers:
-prevent recurrence of paroxysmal supraventricular tachycardia
-decrease ventricular rate in patients with AF

186
Q

Name drugs used in angina which aren’t from the Vaughan Williams classification:

A

Digoxin
Adensoine

187
Q

Describe what normally happens in cardiomyocytes:

A

Normally, Na leaks into and K leaks out of the myocyte cells
A/P increases Na in and K out of myocytes
Na/K ATPase pump normally restores levels

188
Q

Describe the MoA of digoxin:

A

Cardiomyocytes inhibition of Na/K ATPase
Reversal of Na/Ca exchanger
Increase intracellular Ca levels
Inhibition increases Na inside myocytes
Na/Ca exchanger pumps Na out and Ca into myocytes (reversed function) so increased Ca in myocytes increases force of contraction

189
Q

How does adenosine work?

A

Binding to receptor will reduce firing of sinus node
Working on pacemaker cells

190
Q

Describe the MoA of adenosine:

A

A1 receptor (coupled to Gi), inactivate adenylate cyclase, decrease cAMP so decreases chronotrophy so decreases dromotropy
Decreases A/P in pacemaker cells so extends time between A/P in SA node

191
Q

How is cholesterol synthesised?

A

ACoA (precursor molecule)
AcetoaceytlCoA
HMGCoA
L-mevalonate (via HMGCoA reductase- the rate limiting enzyme)

192
Q

Describe the MoA of statins:

A

Competitive and reversible
Inhibits HMG CoA reductase
Decreases cholesterol synthesis in the liver
In liver up regulates LDLr leading to LDLC clearance from plasma to liver

193
Q

Describe statins as a drug:

A

More effective at reducing cholesterol than other drugs-first line
Not great for moderate to high PGs
Reduce CV events and mortality irrespective to initial cholesterol conc

194
Q

Name and describe the faster acting statins:

A

Simvastatin and pravastatin
Specific, reversible, competitive HMG-CoA reductase inhibitors (Ki 1nm)
Extensively metabolised by Cyp450 and glucuronidation
Simvastatin- inactive prodrug metabolised in liver to active form

195
Q

Name the longer lasting statins:

A

Atorvastatin
Rosuvastatin

196
Q

What are the outcomes of lipid profile of statins in circulation?

A

ApoB100 binds to LDLr so uptake of LDL
Increase LDLr mediated hepatic uptake of LDL and VLDL remains so:
-decrease in serum LDL-C
-decrease in serum VLDL remnants
-decrease serum IDL

197
Q

What other protective effects can statins have?

A

Plaque stability
Antithrombotic
Antioxidant
Anti-inflammatory

198
Q

Describe the plaque stability effects of statins?

A

When a person already has atherosclerosis
Decrease cell infiltrate, MMP
Increase collagen, VSMC, TIMP (matrix proteins)
Increase neovascularization (new BVs) of ischaemic tissue (blood supply to decreased areas of blood supply)

199
Q

Describe the anti-thrombotic effects of statins:

A

Decrease TF, PAI-1, platelet aggregation (stop blood clots forming)
Increase fibrinolytic activity, tPA, eNOS

200
Q

Describe the anti-oxidant effects of statins:

A

Decrease NADPH oxidase, superoxide, oxidation of LDL (pro oxidants)
Increase free radical scavengers (increase removal of damaging oxidative species)

201
Q

Describe the anti-inflammatory effects of statins:

A

Decrease NFkB, IL1,TNF,MMP,CRP
Leukocyte-endothelial interactions
Adhesion molecules
Macrophage/T cell activation
Complement injury
SM cell proliferation
Monocyte chemotaxis

202
Q

Describe the genetic variation influence response to statins:

A

Polymorphism of CYPs which metabolise statins:
-3A4,3A5,2C8,2C9,2D6
ABCs (transporters that get statins into cells):
- A1,G1,G5,G8,B1,C2
HMG CoA reductase
Lipoprotein lipase (breaks down TGs)
Apoproteins
Choleteryl ester transfer protein
PPARa (nuclear receptors)
SREBP1 and 2
IL1B,IL6 polymorphisms influence response to pravastatin

203
Q

Describe the absorption of statins:

A

Limited systemic bioavailability:
50-80% will still be in an active form after first pass metabolism- not too bad as want it to work in liver but other effects may be decreased

204
Q

Describe the effectiveness of stains:

A

Some work better at night as HMG CoA reductase changes activity throughout the day (as don’t take food at night)
Typical LDL reduction from 20-40% (lovastatin) to 40-60% (atorvastatin)
10-20% decrease in TGs
5-10% increase in HDLs

205
Q

What are the links between statins and T2D?

A

Benefits outweigh the harm in high risk patients- increase risk of developing T2D with more lipophilic statins
Studies in COPD (no benefit), pneumonia, cancer, spinal cord injury, mainly lack of evidence

206
Q

What are fibrates?

A

Derivatives of fibric acid (occasionally used in hypertiglycerdaemia)
Structurally related thiazolidnediones

207
Q

Name examples of fibrates:

A

Bezafibrate
Ciprofibrate
Gemofibrozil
Fenofibrate

208
Q

Describe the MoA of fibrates:

A

Agonists of PPARa- bind to them

209
Q

What are PPARa?

A

Subfamily of nuclear receptors that modulate lipid and carbohydrate metabolism and induce differentiation of adipocytes

210
Q

What is the MoA of PPARa?

A

Increase lipoprotein lipase- results in breakdown of VLDL
Induce ApoA1 and ApoA5 results in increase of HDL production

211
Q

What is the MoA of fibrates as well as their PPARa mechanism?

A

Increase hepatic LDL-C uptake, form LDL with higher affinity to the LDLr so decrease serum conc
Increase FA uptake and conversion of acylCoA by the liver therefore FAs aren’t available for TG synthesis
Decrease of VLDL from liver and hence TG levels decrease
Anti-inflammatory effects

212
Q

What are the anti-inflammatory effects of fibrates?

A

Decrease APP synthesis- CRP and fibrinogen
Inhibit Vascular Smooth Muscle Cell (VSMC) inflammation via suppressing NFkB

213
Q

Which proteins do fibrates affect and therefore its consequence?

A

Increase in, which increases HDL
ApoAI
ApoAII
ABCA1
Decrease in ApoCIII which decrease VDL
Increase in AcylCoA synthase so decreases FFA
Decrease in LDL particles and size

214
Q

What is the clinical use of fibrates?

A

Not routinely recommend by NICE
Can be prescribed for hypertriglyceridemia if serum TG>10mmol/L
Given when statins are CI or not tolerated

215
Q

Name and describe other drugs that can inhibit cholesterol absorption:

A

Ezetimibe
Bile acid binding resins- no longer recommend except in special circumstances as can aggregate hypertigylceridamia
Plant stanols and sterols- supplements and functional foods, plant cholesterol instead of animal cholesterol so can’t be used in the same way in the body so doesn’t have those damaging effects

216
Q

Describe the MoA of ezetimibe:

A

Specifically blocks absorption of cholesterol in intestine without affecting absorption of fats soluble vitamins, TG or bile acids
Higher potency than bile acid resins because specifically proteins in GI epithelial cells that are responsible for cholesterol absorption, including:
-NPC1L1, aminopeptidase N and caveolin-1-Annexin A2 complex

217
Q

How is ezetimibe metabolised and excreted?

A

Conjugated in the intestine to ezetimibe glucuronide (also pharmacologically active) and excreted in the stools
No important drug or food interactions

218
Q

How effective is ezetimibe?

A

Lowers LDL-C by 17%

219
Q

Describe Nicotinic acid derivatives:

A

Nicotinic acid-water soluble VitB
1.5-3g a day
No longer recommend by NICE for 1º/2º prevention of CAD, CKD or diabetes because of vasodilatory effects
Occasional use in combo with statin if not adequately controlled

220
Q

Describe the MoA of niacin:

A

Decreases mobilisation of free FAs so increase uptake in the liver
So decreases TG synthesis, decreases VLDL secretion in hepatocytes
So decrease serum VLDL results in decrease lipolysis to LDL
Decrease serum LDL
Increase HDL in systemic circulation

221
Q

What normally happens in receptor recycling for cholesterol without PCSK9?

A

Hepatocyte has expression of LDLr
LDL interactions with LDLr and enters hepatocyte by endocytosis, in the endosome the LDLr is taken away from the LDL particle which means cholesterol and TG release in liver so LDLr recycled back onto cell membrane

222
Q

What does PCSK9 stand for?

A

Proprotein Convertase Subtilisin/Kexin type 9

223
Q

What happens in receptor recycling with PCSK9?

A

PCSK9 can stop receptor recycling, binds to LDLr as well as LDL particle, it is taken up into the hepatocyte cell and the whole complex is broken down to lysosome so no recycling so less LDL taken up so increase in serum cholesterol

224
Q

Name 2 PCSK9 inhibitors:

A

Alirocumab
Evolocumab

225
Q

Describe PCSK9 inhibitors:

A

Treatment of 1º hypercholesterolemia or mixed dyslipidamiea conjunct to diet
Combo with statin or other lipid lowering drug if statin not tolerated (2nd line as newer and more expensive)
Approved by NICE

226
Q

Describe the MoA of PCSK9 inhibitors:

A

MAB that inhibits PCSK9, results in increase receptor number and LDL uptake
Anti PCSK9 Ab binds to PCSK9 preventing it from binding to the LDLr, so more LDLr are recycled to the cell surface and continue to clear LDL particles

227
Q

Describe Inclisiran as a treatment for hypercholesterolemia:

A

NICE approved
A small interfering RNA (siRNA) treatment
Blocks the change of mRNA to protein
Inhibit the translation of PCSK9 mRNA leads to gene silencing- stops it being put into a protein

228
Q

Describe the MoA of Inclisiran:

A

Uptake of siRNA into hepatocyte, released from endoscopes
Interacts with RNA induced silencing complex (RISC) which cuts the mRNA of PCSK9 so no protein made
Decrease PCSK9 protein in hepatocyte, so less interfering with LDLr

MPharm Y3S1 (13 decks)

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