CVD Pharmacology Flashcards
(228 cards)
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
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
3
Q
Name the 2 atrial ventrical valves:
A
Bicuspid (mitral)- left, 2 leaflets
Tricuspid- right, 3 leaflets
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
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
6
Q
What is the brief definition of diastole?
A
Heart is relaxing and filling- isovolumetric ventricular relaxation
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
8
Q
What is the brief definition of systole?
A
Contraction and emptying of the heart- isometric ventricular contraction
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
10
Q
What is end systolic volume?
A
Amount of blood in ventricle at end of systole
11
Q
What is end diastolic volume?
A
Amount of blood at end of diastole
12
Q
How much blood has to be in the heart before an arterial contraction?
A
80% filled
13
Q
What is the equation for stroke volume?
A
End diastolic volume- end systolic volume
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
15
Q
Describe the pericardial sac and its function:
A
Double walled sac
Tough covering- anchors heart
Secretory lining- pericardial fluid, lubricaiton
16
Q
What is pericarditis?
A
Painful rubbing
Viral/bacterial
Fluid becomes inflamed
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
18
Q
Briefly describe the heart beat:
A
Simultaneous dual pump
Each beat triggers by depolarisation via an action potential
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
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
21
Q
Where do cardiomyocytes pass the action potential?
A
From purkinje fibres to next cardiomyocyte
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
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
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
25
What are the affects of abnormal levels of K+ on the resting potential?
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
26
What are the affects of abnormal Ca2+ levels on the resting potential?
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
27
What is the cardiac refractory period?
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
28
What is the P wave in an ECG?
Depolarisation of atria in response to SA node triggering AP (atria depolarisation)
29
What is the PR interval in an ECG?
Delay of AV node to allow filling of ventricles
30
What is the QRS complex in an ECG?
Depolarisation of ventricles, triggers main pumping contractions- main contraction of the heart
31
What is the ST segment in an ECG?
Beginning of ventricle repolarisation, should be flat
32
What is the T wave in an ECG?
Ventricular re-polarisation
33
What can an ECG be a diagnosis of?
Abnormalities in Rate
Abnormalities in Rhythm:
-atrial flutter
-atrial fibrillation
-ventricular fibrillation
-heart block
Cardiomyopathies
-ischemia
-infarct
34
How do you label a carboxylic acid?
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
35
What is oleic acid?
Omega 9
18C and double bond found at position 9
36
What is linoleic acid
Omega 6
Polyunsaturated FA
Double bond found on 6th carbon
37
What is a-Linolenic acid?
Omega 3
Polyunsaturated FA
Double bond found on 3rd carbon
38
Why do we need fats for?
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
39
How is fat digested and absorbed?
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
40
How are lipoproteins transported?
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
41
What is the density like of lipoproteins with more/less lipid and cholesterol?
Lipoproteins with more proteins are generally more dense as proteins are heavier than lipids
Lipoproteins with more lipids are lower density
42
What are apoproteins?
Act as ligand on different receptors on body, helps uptake of lipoprotein, depends on type of apoprotein as to where its taken up
43
Name the 5 classes of lipoproteins:
Chylomicrons- fat absorption from intestine
Very low density lipoproteins (VLDL)
Low density lipoproteins (LDL) -bad
Intermediate density lipoproteins (IDL)
High density lipoproteins (HDL) -good
44
Describe chylomicrons:
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
45
Describe VLDL:
Main component TG
Diameter 30-80µm
Density 0.95-1.006
Apoproteins B100 (A,C,E)
46
Describe IDL:
Have a mix of both TG and cholesterol
Diameter 25-31
Density 1.006-1.019
Apoproteins B100 (E)
47
Describe LDL:
Main component is cholesterol
Diameter 18-25
Density 1.019-1.063
Apoproteins B100
Bad as can leave behind cholesterol deposits
48
Describe HDL:
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
49
Describe the pathway for exogenous lipids:
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
50
Describe the pathways for endogenous lipids using LDLs:
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
51
Describe the pathways for endogenous lipids using HDLs:
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)
52
What drugs can work on the exogenous lipid pathway and how?
Ezetimibe decreases absorption of cholesterol from going to chylomicrons
53
What drugs can work on the endogenous lipid pathway and how?
Statins, resins and fibrates increase re-uptake of LDL into coated pits of hepatocytes
Statins also decrease synthesis of cholesterol
54
What is the function of ApoB48?
In chylomicrons, essential for intestinal absorption of dietary lipids
55
What is the function of ApoE?
In chylomicrons, mediates uptake of chylomicron remnants into liver by LDL receptor
56
What is the function of ApoB100?
In VLDL, LDL and LDL, main physiological ligand for LDLr and synthesised in the liver
57
What is the function of ApoA1?
In HDL, promotes cholesterol efflux from tissues to liver for excretion
58
Where are LDL receptors found?
On all nucleated cells
Increased expression on hepatocytes
59
Describe the joint stage in the LDL receptor pathway:
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
60
Describe the LDL receptor pathway for the free LDL vesicle:
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
61
Describe the LDL receptor pathway for the LDLr vesicle:
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
62
Describe Reverse Cholesterol Transport:
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
63
Name the lipid transfer proteins involved in lipid transport:
ACAT- acetyl CoA- cholesterol acyltransferase
LCAT- lecithin cholesterol acyltransferase
CETP- cholesterol ester transfer protein
PLTP- phospholipid transfer protein
64
What is the function of ACAT?
Catalyses intracellular synthesis of cholesteryl ester in macrophages, adrenal cortex, gut and liver
Tamoxifen is a potent ACAT inhibitor
65
What is the function of LCAT?
Catalyses cholestryl ester synthesis in HDL particles
66
What is the function of CETP?
Transfer of cholestryl ester between HDL to IDL or VLDL
67
What is the function of PLTP?
Transfer of cholesterol and TG between different classes of lipoprotein particles in plasma
CETP inhibition is a potential therapeutic strategy
68
What is dyslipidemia?
Disorder of lipid metabolism including lipoprotein overproduction and deficiency
69
What can be the causes of dyslipidemia?
Increase in total cholesterol (TC)
Increase in LDL (increase deposited in arteries)
Increase in triglyceride
Decrease in HDL
70
Describe the first stage of atherosclerosis:
Form of injury e.g smokers, diabetes
-endothelial permeability
-leukocyte migration
-endothelial adhesion
-leukocyte adhesion
71
Describe the second stage of atherosclerosis:
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
72
Describe the third stage of atherosclerosis:
Plaque gets bigger
-Macrophage accumulation
-formation of necrotic core- blood isn't reaching cells
-fibrous cap formation
73
Describe the fourth stage of atherosclerosis:
Fibrous cap thins and plaque rupture
Haemorrhage from plaque micro vessels leads to a HA or stroke
74
How much LDL is part of TC and what is its main function?
60-70% of TC
Oxidised and deposited in BVs, leads to atherosclerosis
75
How much HDL is part of TC and what is its main function?
20-30% of TC
Transports excess cholesterol from peripheral tissues to liver
Antioxidant- decreases adverse effects from LDL
76
What is the epidemiology of dyslipidemia?
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
77
Describe the aetiology of primary dyslipidemia:
60% have primary
Combination of diet and genetics
Genetics-5 inherited conditions
Diet and lifestyle
78
What are the diet and lifestyle factors which cause primary dyslipidemia?
High saturated fat
Smoking
Physically inactive
Overweight/obese
Large waist circumference
79
Describe the aetiology of secondary dyslipidemia:
40% have secondary
Underlying cause:
Disease or certain drug e.g thiazides, diabetes, liver disease, GC
Natural rise as age and after menopause
80
Name and describe inherited conditions that increase blood lipids:
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
81
Name different types of primary dyslipidemia:
Familial combined hyperlipidemia
Type 3 hyperlipidaemia
Polygenic hypercholestrolaemia
Primary hypertriglyceridaemia
Lysosomal acid lipase deficiency
82
Describe familial combined hyperlipidemia:
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
83
Describe type 3 hyperlipidaemia:
Inherited 1/5000-1/10000
High cholesterol and triglyceride
Mutations of ApoE
84
Describe polygenic hypercholesterolaemia:
More than 1 gene with changes
>12 genes linked to high cholesterol
85
Describe primary hypertriglyceridaemia:
Lipoprotein lipase deficiency
Affects 1 in a million
Very high triglyceride
86
Describe lysosomal acid lipase deficiency:
Breaks down fat into lysosomes normally but instead, fat builds up
Rare condition affects less than 1 in a million in UK
87
Name and describe the eyeball sign of hyperlipidaemia:
Corneal arcus
Cholesterol deposition around outer eye- grey ring on iris
88
Name and describe the skin signs of hyperlipdaemia:
Tendon xanthomas- raised areas on skin (elbows)
Xanthelsma- patches around eyes where cholesterol deposited
89
What underlying disorders can cause secondary dyslipidaemia?
Diabetes
Hypothyroidism
Chronic renal failure
Alcoholism
Liver disease
90
What drugs can cause secondary dyslipdaemia?
Thiazide diuretics
Loop diuretics
B blockers
Oral contraceptives
Ciclosporin
GCs
Isotretinoin
Tamoxifen
Protease inhibitors of HIV
91
Describe how lipoprotein (a) is a risk factor for thrombosis:
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
92
What are the non-pharmacological treatment of dyslipidaemia?
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
Name the segments of the endothelial:
Inner most endothelial-detect blood flow
Middle smooth muscle cells and elastic components- BP
Outer- apprenticial layer
94
Describe the process for atherosclerosis:
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
What is hemostasis?
Arrest of blood loss from damaged BVs
96
Describe the stages in hemostasis:
Wound
Vasoconstriction
Platelet activation and adhesion-> thrombosis
Formation of haemostatic plug (coagulation)
Fibrinolysis
97
What is thrombosis?
Pathological formation of clot in vasculature in the absence of bleeding
98
What can drugs target to affect haemostats and thrombosis?
Platelet adhesion and activation
Blood coagulation (fibrin formation)
Fibrin removal (fibrinolysis)
99
What conditions are used for haemostasis promotion?
Haemophilia
Extensive anticoagulation therapy
Haemorrhage after surgery
Menorrhagia
100
Describe the function of platelets:
Maintain integrity of circulation
Essential for haemostasis, healing of vessels and inflammation, formation of thrombi, first step in clotting cascade
101
Describe the properties of platelets:
Adhesion following vascular damage
Shape change
Secretion of granule contents
Biosynthesis of PAF and PGs
Aggregation
Exposure of acidic phospholipid on surface
102
When are platelets active?
Not normally active
Activated when exposed to damage
103
What components of the extracellular matrix can activate platelets?
Von Willebrand factor (wWf)
Collagen
Platelets have receptors for these
104
What soluble factors do platelets have receptors for?
ThromboxaneA2
ADP
105
How can platelet aggregation lead to further activation?
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
What are factors that prevent/limit the activation of platelets?
NO, PGI2- both made by endothelial cells of the blood
Enzymes (CD39) which remove ADP to AMP
107
What are ways of inhibiting platelet aggregation/activation?
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
What are factors that activate platelets?
ADP binding
TXA2
Fibrinogen (GP IIb/IIIa)
109
Name different classes of anti platelet drug:
Aspirin
Thienopyridines-clopidogrel, prasugrel
Ticagrelol
Glycoprotein IIb/IIIa inhibitors:
-eptifibatide
-tirofiban
-abciximab
110
What are the different functions in terms of COX 1 and 2 for platelets?
COX 1 in platelet for TXA2 production
COX 2- platelet aggregation inhibitor, PGI2
111
Why does aspirin work as an anti platelet even though it inhibits PGI2?
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
How do thienopyridines work?
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
How does Ticagrelor work?
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
Describe the advantages of Ticagrelor:
PLATO trial- ticagrelor less mortality from all CV causes than clopidogrel
Sts-more non lethal bleeding but effects more quickly reversible though
115
How does the Glycoprotein IIB/IIIa receptor normally work?
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
How do GP IIb/IIa receptor antagonists work?
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
Describe the stages in coagulation:
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
What is coagulation?
Formation of a fibrin clot or thrombus
Reinforces platelet plug
May trap BCs
-white thrombus -red thrombus
119
Name and describe the 2 types of coagulation cascades:
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
Describe the coagulation cascade for both intrinsic and extrinsic cascade:
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
How is the platelet plug formed?
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
Describe the role of thrombin:
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
What are the roles of the liver?
Synthesises clotting factor
Vit K (phytomenadione):
Synthesis of bile salts- vit K reabsorption
124
What are the roles of vitamin K?
-'koagulation' vitamin
-lipid soluble
-required for synthesis of factors II,VII,IX,X
-dietary source
-synthesis of vit K in GIT
125
What are the main drugs to treat platelet rich white thrombi?
Antiplatelet drugs- aspirin
126
What are the main drugs to treat platelet rich red thrombi?
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
Why does warfarin have to be monitored so closely?
Warfarin can inhibit factor 9 and 10 and prothrombin and also factor 7 of the extrinsic pathway- lots of factors
128
Where are heparins found?
Extracted from the liver, present in mast cells
129
Describe the MoA of heparins:
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
Describe the structure of heparin:
Highly acidic sulphate groups- administered as heparin sodium
131
What is the family of heparins?
GAGs (mucopolysaccharides)
132
Name the 2 different compounds of heparin:
Unfractionated (UFH)-combo of all heparins
Low molecular weight heparins (LMWH)-purified
133
Which one of the heparin compounds are more predictable and why?
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
Describe the pharmacokinetics of heparin:
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
What are the advantages of using LMWH of UFH?
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
State how warfarin works:
Inhibits vit K reductase
Competitive inhibition
137
What are the effects of vitamin K inhibition?
Inhibits hepatic vitamin K dependant synthesis of factors II,VII,IX and X and of anticoagulation protein C and its cofactor proteins
138
What are the disadvantages of using warfarin?
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
Describe the pharmacokinetics of warfarin:
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
Describe the outline fibrinolytic system:
When homeostasis has been restored
Clot removal
-fibrinolytic pathway
-plasmin formation/activation
-potent proteolytic enzyme (attacks fibrin at 50 different sites)
141
How is plasmin formed and activated?
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
Describe the details/process of the fibrinolytic system:
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
Describe the inhibitors of the fibrinolytic system:
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
Name the drugs that stimulate fibrinolysis and how?
They can convert plasminogen to plasmin:
-streptokinase
-Recombinant human tPA
--reteplase and tenecteplase
--alteplase
-Urokinase
145
Describe the features of streptokinase:
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
Describe the features of Altepase:
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
Describe the features of reteplase and tenecteplase:
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
Describe the features of urokinase:
uPA
not selective for clot bound fibrin so less useful
149
What is angina pectoris?
Tight chest
Symptom of a disease which is probably atherosclerosis
When oxygen supply to myocardium is insufficient for its needs
150
Describe the symptoms of angina:
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
What is atherosclerosis?
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
What are the aims of treatment for angina/ atherosclerosis?
Alleviate acute symptoms
Minimise frequency of ischaemia
Decrease progression of atherosclerosis (2º prevention e.g statins, aspirin ACEi etc)
153
What are the triggers for angina?
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
What are ways to reduce oxygen demand?
Reduce cardiac workload
Reduce cardiac rate/contractility
Increase efficiency of the heart
155
How would you reduce cardiac workload?
Decrease perfusion demands:
-e.g rest, stress, smoking, weight
Decrease preload:
-venodilator e.g nitrates
Decrease afterload:
-arterial dilatory e.g CCBs, nitrates
156
How would you reduce cardiac rate/contractility?
Veinotrope/ chronotrope e.g B blocker, CCB
157
How would you increase the efficiency of the heart?
Exercise
Stop smoking
158
What are ways to improve oxygen supply?
Increase coronary flow
-arterial dilator e.g CCB, nitrate
-surgery e.g bypass, angioplasty, stent
159
Name anti-anginal agents:
*Organic nitrates- acute attacks, mimic NO
*CCBs
*B adrenoreceptor antagonists- slow HR
Potassium channel activators
-vasodilators
160
Name and describe examples of organic nitrates:
Glycerol trinitrate:
-explosive
-effective in angina
-quick onset, short DoA
Isosorbide mononitrate
-longer DoA
161
Describe how nitrates work, at lower doses:
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
What do nitrates cause at higher doses?
Not ideal
Arteriolar dilation, fall in BP, reduced CO, headache
163
How is NO produced normally as a vasodilator?
Endothelial cells will recognise shear stress releasing NO
NO diffuses across membranes into SM cells leading to vascular relaxation
164
How does NO cause vascular relaxation?
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
Describe the effects of nitrates on coronary circulation:
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
Describe the pharmacokinetics of nitrates:
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
How do B blockers work for angina?
Decreases oxygen consumption only
Depress the myocardium (-ve inotropy)
168
How do B blockers decrease O2 consumption only?
Slows the heart (-ve chronotropy)
169
How do B blockers depress the myocardium?
No effect on coronary arteries
Provide 2º prevention
Increase exercise capacity
CI in coronary spasm
Slow withdrawal (up regulate receptors)
170
What are the indications of B blockers for angina?
Angina prophylaxis
Unstable angina
171
What are the 3 main classes of CCBs and name a few:
Phenylalkylamines e.g verapamil
Dihydropyridines e.g nifedipines, amlodipine
Benzothiazepines e.g diltiazem
172
How do CCBs work?
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
Describe where the different classes of CCBs can work:
Verapamil is relatively cardioselective
Nifedipine is relatively sm selective
Diltiazem is intermediate
174
Describe the cardiac actions of CCBs:
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
Describe the vascular SM actions of CCBs:
Mainly nifedipine
Arteriolar dilation, decreases BP, decreasing afterload
Coronary vasodilation- used in patients with variant angina (spasm)
176
What is a cardia arrhythmia?
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
Describe the Vaughan Williams classification:
Drug classification:
IA (moderate)
IB (weak)
IC (strong)
II
III
IV
178
What drugs will work on class 1 of Vaughan Williams classification?
Na+ channel blockers, depends on how they affect A/P
IA- procainamide, quinidine
IB- lidocaine, phenytoin
IC- flecainide, propafenone
179
Describe the function of class 1 drugs in the Vaughan Williams classification:
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
What drugs will work on class 2 of Vaughan Williams classification?
B adrenoreceptor blockers
Propranolol, metoprolol
181
Describe the function of class 2 drugs in the Vaughan Williams classification:
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
What drugs will work on class 3 of Vaughan Williams classification?
K+ channel blocker:
Amiodarone (has class I,II,III,IV activity)
Sotalol (also a Bblocker)
Ibutilide
183
Describe the function of class 3 drugs in the Vaughan Williams classification:
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
What drugs will work on class 4 of Vaughan Williams classification?
CCBs
verapamil, diltiazem
185
Describe the function of class 4 drugs in the Vaughan Williams classification:
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
Name drugs used in angina which aren't from the Vaughan Williams classification:
Digoxin
Adensoine
187
Describe what normally happens in cardiomyocytes:
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
Describe the MoA of digoxin:
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
How does adenosine work?
Binding to receptor will reduce firing of sinus node
Working on pacemaker cells
190
Describe the MoA of adenosine:
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
How is cholesterol synthesised?
ACoA (precursor molecule)
AcetoaceytlCoA
HMGCoA
L-mevalonate (via HMGCoA reductase- the rate limiting enzyme)
192
Describe the MoA of statins:
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
Describe statins as a drug:
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
Name and describe the faster acting statins:
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
Name the longer lasting statins:
Atorvastatin
Rosuvastatin
196
What are the outcomes of lipid profile of statins in circulation?
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
What other protective effects can statins have?
Plaque stability
Antithrombotic
Antioxidant
Anti-inflammatory
198
Describe the plaque stability effects of statins?
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
Describe the anti-thrombotic effects of statins:
Decrease TF, PAI-1, platelet aggregation (stop blood clots forming)
Increase fibrinolytic activity, tPA, eNOS
200
Describe the anti-oxidant effects of statins:
Decrease NADPH oxidase, superoxide, oxidation of LDL (pro oxidants)
Increase free radical scavengers (increase removal of damaging oxidative species)
201
Describe the anti-inflammatory effects of statins:
Decrease NFkB, IL1,TNF,MMP,CRP
Leukocyte-endothelial interactions
Adhesion molecules
Macrophage/T cell activation
Complement injury
SM cell proliferation
Monocyte chemotaxis
202
Describe the genetic variation influence response to statins:
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
Describe the absorption of statins:
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
Describe the effectiveness of stains:
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
What are the links between statins and T2D?
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
What are fibrates?
Derivatives of fibric acid (occasionally used in hypertiglycerdaemia)
Structurally related thiazolidnediones
207
Name examples of fibrates:
Bezafibrate
Ciprofibrate
Gemofibrozil
Fenofibrate
208
Describe the MoA of fibrates:
Agonists of PPARa- bind to them
209
What are PPARa?
Subfamily of nuclear receptors that modulate lipid and carbohydrate metabolism and induce differentiation of adipocytes
210
What is the MoA of PPARa?
Increase lipoprotein lipase- results in breakdown of VLDL
Induce ApoA1 and ApoA5 results in increase of HDL production
211
What is the MoA of fibrates as well as their PPARa mechanism?
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
What are the anti-inflammatory effects of fibrates?
Decrease APP synthesis- CRP and fibrinogen
Inhibit Vascular Smooth Muscle Cell (VSMC) inflammation via suppressing NFkB
213
Which proteins do fibrates affect and therefore its consequence?
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
What is the clinical use of fibrates?
Not routinely recommend by NICE
Can be prescribed for hypertriglyceridemia if serum TG>10mmol/L
Given when statins are CI or not tolerated
215
Name and describe other drugs that can inhibit cholesterol absorption:
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
Describe the MoA of ezetimibe:
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
How is ezetimibe metabolised and excreted?
Conjugated in the intestine to ezetimibe glucuronide (also pharmacologically active) and excreted in the stools
No important drug or food interactions
218
How effective is ezetimibe?
Lowers LDL-C by 17%
219
Describe Nicotinic acid derivatives:
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
Describe the MoA of niacin:
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
What normally happens in receptor recycling for cholesterol without PCSK9?
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
What does PCSK9 stand for?
Proprotein Convertase Subtilisin/Kexin type 9
223
What happens in receptor recycling with PCSK9?
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
Name 2 PCSK9 inhibitors:
Alirocumab
Evolocumab
225
Describe PCSK9 inhibitors:
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
Describe the MoA of PCSK9 inhibitors:
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
Describe Inclisiran as a treatment for hypercholesterolemia:
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
Describe the MoA of Inclisiran:
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
