CVD Pharmacology Flashcards
What is a lipoprotein
Lipids and cholesterol transported in blood as complexes of lipids and proteins
Hydrophobic core of lipid
Hydrophilic phospholipids, cholesterol and apoprotein
What are the types of lipoproteins
Chylomicrons (biggest) TG
Very low density lipoproteins TG
Low density lipoproteins TG and cholesterol
Intermediate density lipoproteins cholesterol
High density lipoproteins (smallest) proteins
How are cholesterol and TGs absorbed
From diet-> ileum -> chylomicrons-> lymph->blood-> muscle and adipose tissue
TG hydrolysed by lipoprotein lipase -> glycerol and fatty acids
Cholesterol stored if remaining chylomicrons
What lipoproteins are absorbed and in what stage?
Cholesterol and new TG travel as VLDL
Lipoproteins get smaller but keep cholesterol esters and become LDL and bind to receptors
Cholesterol deposited in tissues
Cholesterol can return to plasma via HDL (reverse cholesterol transport)
Cholesterol esterified with LCFA in HDL and transferred to VLDL or LDL by cholesterol ester transfer protein
How are cholesterol esters up taken by cells by the LDL receptors
Coated pit -> vesicle -> endosome -> recycling vesicle -> coated pit again
What is reverse cholesterol transport
Cholesterol from tissues back to liver
HDL made in liver- protein rich and no cholesterol
When circulating- takes up cholesterol
Forms spherical HDL3
CETP transfers cholesterol esters and HDL taken back to liver where hepatocytes excrete the cholesterol it contains
What is CETP
cholesteryl ester transfer protein
Transfers cholesteryl ester between HDL to IDL or VLDL
What is dyslipidaemia
Disorder of lipid metabolism (lipoprotein over production and deficiency)
What are the stages of atherosclerosis
Injury in endothelial cells of blood vessels
Adhesion molecules and monocytes bind
Blood vessels take up oxidised LDL and combines with macrophages (FORMS FOAM CELLS)
Foam cells under endothelial layer cause plaque - immune response!
More plaque causes necrotic core and fibrous cap on top forms
If ruptures then heart attack/stroke
What is the target for cholesterol
less than 5mmol/l
But 40% decrease in Non-HDL is the aim
What are some non-pharmalogical treatments of dyslipidaemia
Decrease sat and trans fats, increase unsat. fats= decr. LDL and incr. HDL
Oily fish
Plant sterols to decrease cholesterol abs.
Incr. fibre
Weight loss
smoking
30mins 5x a week activity
decrease alcohol
What do statins do
HMG-CoA reductase
Competitive and reversible
Decreases cholesterol synthesis
Increases LDL receptors
Decrease blood LDL as increases cholesterol uptake
RLS- catalyses conversion of HMG-CoA to mevalonic acid - prevents mevalonate production
What is simvastatin and pravastatin metabolised by
CYP450
What protective effects do statins offer
plaque stability
Anti thrombotic
Anti-oxidant - decreases NADPH oxidase
Anti-inflammatory - decreases NF-kB
What are fibrates and how do they work
-fibrate usually
agonists for PPARalpha
Increases APOA1, APOA11,ABCA1, APOC111, acyl-CoA synthase
What inhibits cholesterol absorption?
Ezetimibe
plant stanols and sterols
What does ezetimibe do
blocks NPC1L1- blocks abs of cholesterol without affecting vitamins, TGs or bile acids
What is the niacin MOA
Decreased TG synthesis as decreases mobilisation of FFA
Decreases VLDL and ApoB in hepatocytes
What is PCSK9
Proprotein convertase subtilisin/kexin type-9 (pcsk9)
Binds to hepatic LDL receptors and promotes lysosomal degradation of LDL particles
prevents recycling of LDL receptors back onto hepatocyte surface and therefore limits LDL uptake into liver
What is alirocumab and evolucumab
MAB that inhibit PCSK9 increasing receptor number and LDL uptake.
Anti-pcsk9 antibody binds to pcsk9 preventing it from binding to LDL receptor, allowing recycling of expression of LDL receptor
What is Inclisiran
small interfering RNA that inhibits translation of PCSK9 mRNA -> gene silencing!!
Interacts with RISC complex (RNA induced silencing complex)
which degrades mRNA of PCSK9
Less PCSK9 therefore less likely to interfere with LDL receptor expression
What is atherosclerosis
Damage to endothelial cells
LDL cross endothelial layer and accumulates/ oxidises
Markers expressed for immune response
Immune cells pass thru endothelial layer and destroy oxidised LDL
Immune cells -> foam cells
causes smooth muscle cells to form a FIBROUS CAP to stop access to necrotic core
Fibrous cap- plaque can thin and rupture causing blood clot
What is haemostasis
stopping blood loss from damaged blood vessels
wound
vasoconstriction
platelet activation and adhesion
coagulation (haemostatic plug)
Fibrinolysis (resolve coagulation)
What is thrombosis
formation of a clot
What causes platelet activation and adhesion
Damage!
Collagen exposure
Thromboxane A2 and ADP can also activate platelets
Platelet aggregation
Fibrin/fibrinogen
von willebrand factor
prostacyclin
nitric oxide
What do antiplatelets do
decrease platelet aggregation and inhibit thrombus formation
Name some antiplatelets
Aspirin
Thienopyridines (clopidogrel)
Ticagrelor
How does aspirin have anti-platelet activity
Irreversibly inactivates COX (cyclooxygenase)
Prevents thromboxane A2 production in platelets therefore less clotting
Also decreases prostaglandin formation
COX1 IN PLATELETS-| decreases Thromboxane A2 decreasing platelet aggregation
COX2 IN ENDOTHELIUM-| decreases prostaglandins but increases platelet aggregation
Net effect = 0
HOWEVER- endothelial cells synthesize new COX 2 , platelets cant!
Low doses only inhibit platelets, high dose inhibits both COX.
How do thienopyridines (clopidogrel) work as an antiplatelet
Inhibits ADP induced aggregation
Antagonise platelet P2Y12 receptor
How does ticagrelor work as an antiplatelet
Nucleoside analogue - adenosine
Blocks P2Y12 ADP receptors on platelets
Allosteric inhibitor
How do Glycoprotein 11B and 111A receptor antagonists work
Binds to glycoprotein 11b/111a blocking fibrinogen preventing aggregation of platelets
How does coagulation work
Platelets attach to endothelium
They release fibrin and seal endothelium
Fibrin network traps RBC and seals endothelium
Fibrin clot
What is the coagulation cascade
Intrinsic- damaged surface
*xII-> xIIa
*xI-> xIa
*Ix-> Ixa
*x-> xa
* prothrombin(II) -> Thrombin (IIa)
* Fibrinogen (I) -> Fibrin (Ia)
* XIIIa
*Cross linked fibrin clot
Extrinsic -trauma
*VII-> VIIa
* tissue factor causes x-> xa
* prothrombin(II) -> Thrombin (IIa)
* Fibrinogen (I) -> Fibrin (Ia)
* XIIIa
*Cross linked fibrin clot
What is the role of thrombin
Cleaves fibrinogen producing insoluble fibrin
Activated XIII strengthens fibrin links
Platelet aggregation
Role of the liver and coagulation
Koagulation vitamin- VIT K
Makes clotting factors
makes bile salts
Anti-coag agents
warfarin and heparin
How do heparins work
Activates anti thrombin 111
Inactivates thrombin and Xa
What are the types of heparin
Unfractionated (inhibits thrombin and Xa)
Low molecular weight (Mainly inhibits Xa- more predictable)
What are the advantages of Low molecular weight heparin
Binds less to endothelium so has better bioavailability and half life
Predictable dose response
Decreased frequency of dosing
Less side affects- can be used at home
How does warfarin work
Inhibits vitamin K reductase
Competitive
therefore Anticoagulation factors and protein C cant be made
Does warfarin have direct action on clots?
No
Acts indirectly via vitamin K
What are the pharmacokinetics of warfarin
Readily absorbed thru GIT
Binds to plasma proteins
Long half life! 37 hrs
Metabolised by cytochrome P450
Hard to control drug
What is fibrinolytics
where clots are resolved and removed to restore blood flow
Degrades fibrin polymers into smaller products (done by plasmin)
What is plasmin formed by and by what enzymes?
Plasminogen
by:
*Tissue plasmin activators (tPA)
*Urokinase Plasminogen activator (uPA)
*Kallikrein
What drugs stimulate fibrinolysis
streptokinase
Urokinase- less useful/selective
Recombinant human tPA:
*reteplase
*alteplase
*tenecteplase
What is alteplase used for
‘Clot selective’ as active for fibrin bound plasminogen rather than plasma bound
Acute ischaemic stroke, PVT and PE
What 3 classes of drugs are used for angina
Nitrates
Beta blockers
CCBs
What is angina pectoris
its a symptom
Oxygen supply to myocardium is insufficient due to partial blockage or artery spasm
What are angina triggers
Increasing O2 needs and reducing O2 supply
by increasing cardiac workload or having a restricted coronary perfusion
What decreases afterload of the heart
Arterial dilators- CCB and nitrates
What decreases pre-load
Venodilator eg nitrates
How to improve oxygen supply
CCB and nitrates
Surgery- bypass , stent etc
Decrease atherosclerosis
What drugs are used for angina
Organic nitrates
CCBs
B-adrenoreceptor antagonists (slows HR)
Potassium channel activators (vasodilators)
What are some organic nitrates and whats the MOA
Glyceryl trinitrate (nitroglycerin)
Isosorbide mononitrate
Nitric oxide relaxes smooth muscle by Myosin Light Chain- mainly effects heart, decreases pre-load
Low doses good- high doses can mess with BP and causes headache etc
nitrates->Activates guanylate cyclase->cGMP-> Activation of Myosin Light Chain-> vasodilation-> decr. pre-load
What is shear stress
Frictional force parallel to wall
How do BBlockers work for angina
Decreases oxygen consumption
Slows heart
Secondary prevention
Blocks calcium ions entering cells by blocking Voltage gated L-type Calcium channel. Binds to alpha1 subunit of cardiac L-type CaChannels
What BBlocker is contraindicated for heart failure
Verapamil
What do class 1 agents do and what are they
Na transporter blockers
can lengthen, shorten or intensify the action potential in muscle cells in ventricles
What do class 2 agents do and what are they
B-Blockers
Decreases Hr, usually affects SA node
Prevents tachyarrhythmias
What do class 3 agents do and what are they
Potassium Channel blockers
Widen duration of action potential
Also can use sotalol
What do class 4 agents do and what are they
Calcium channel blockers
Works on AV node
How does digoxin work
Inhibits Na/K ATPase
Increases Na inside myocytes/ cells
Increases exchange of Na for Ca
Increases intracellular Ca
Increases contractility of cardiac muscle
