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Yr 3 Cardiovascular > CVD Pharmacology > Flashcards

CVD Pharmacology Flashcards

1
Q

What is a lipoprotein

A

Lipids and cholesterol transported in blood as complexes of lipids and proteins
Hydrophobic core of lipid
Hydrophilic phospholipids, cholesterol and apoprotein

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2
Q

What are the types of lipoproteins

A

Chylomicrons (biggest) TG
Very low density lipoproteins TG
Low density lipoproteins TG and cholesterol
Intermediate density lipoproteins cholesterol
High density lipoproteins (smallest) proteins

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3
Q

How are cholesterol and TGs absorbed

A

From diet-> ileum -> chylomicrons-> lymph->blood-> muscle and adipose tissue
TG hydrolysed by lipoprotein lipase -> glycerol and fatty acids
Cholesterol stored if remaining chylomicrons

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4
Q

What lipoproteins are absorbed and in what stage?

A

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

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5
Q

How are cholesterol esters up taken by cells by the LDL receptors

A

Coated pit -> vesicle -> endosome -> recycling vesicle -> coated pit again

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6
Q

What is reverse cholesterol transport

A

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

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7
Q

What is CETP

A

cholesteryl ester transfer protein
Transfers cholesteryl ester between HDL to IDL or VLDL

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8
Q

What is dyslipidaemia

A

Disorder of lipid metabolism (lipoprotein over production and deficiency)

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9
Q

What are the stages of atherosclerosis

A

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

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10
Q

What is the target for cholesterol

A

less than 5mmol/l
But 40% decrease in Non-HDL is the aim

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11
Q

What are some non-pharmalogical treatments of dyslipidaemia

A

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

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12
Q

What do statins do

A

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

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13
Q

What is simvastatin and pravastatin metabolised by

A

CYP450

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14
Q

What protective effects do statins offer

A

plaque stability
Anti thrombotic
Anti-oxidant - decreases NADPH oxidase
Anti-inflammatory - decreases NF-kB

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15
Q

What are fibrates and how do they work

A

-fibrate usually
agonists for PPARalpha
Increases APOA1, APOA11,ABCA1, APOC111, acyl-CoA synthase

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16
Q

What inhibits cholesterol absorption?

A

Ezetimibe
plant stanols and sterols

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17
Q

What does ezetimibe do

A

blocks NPC1L1- blocks abs of cholesterol without affecting vitamins, TGs or bile acids

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18
Q

What is the niacin MOA

A

Decreased TG synthesis as decreases mobilisation of FFA
Decreases VLDL and ApoB in hepatocytes

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19
Q

What is PCSK9

A

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

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20
Q

What is alirocumab and evolucumab

A

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

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21
Q

What is Inclisiran

A

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

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22
Q

What is atherosclerosis

A

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

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23
Q

What is haemostasis

A

stopping blood loss from damaged blood vessels

wound
vasoconstriction
platelet activation and adhesion
coagulation (haemostatic plug)
Fibrinolysis (resolve coagulation)

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24
Q

What is thrombosis

A

formation of a clot

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25
Q

What causes platelet activation and adhesion

A

Damage!
Collagen exposure
Thromboxane A2 and ADP can also activate platelets
Platelet aggregation
Fibrin/fibrinogen
von willebrand factor
prostacyclin
nitric oxide

26
Q

What do antiplatelets do

A

decrease platelet aggregation and inhibit thrombus formation

27
Q

Name some antiplatelets

A

Aspirin
Thienopyridines (clopidogrel)
Ticagrelor

28
Q

How does aspirin have anti-platelet activity

A

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.

29
Q

How do thienopyridines (clopidogrel) work as an antiplatelet

A

Inhibits ADP induced aggregation
Antagonise platelet P2Y12 receptor

30
Q

How does ticagrelor work as an antiplatelet

A

Nucleoside analogue - adenosine
Blocks P2Y12 ADP receptors on platelets
Allosteric inhibitor

31
Q

How do Glycoprotein 11B and 111A receptor antagonists work

A

Binds to glycoprotein 11b/111a blocking fibrinogen preventing aggregation of platelets

32
Q

How does coagulation work

A

Platelets attach to endothelium
They release fibrin and seal endothelium
Fibrin network traps RBC and seals endothelium

Fibrin clot

33
Q

What is the coagulation cascade

A

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

34
Q

What is the role of thrombin

A

Cleaves fibrinogen producing insoluble fibrin
Activated XIII strengthens fibrin links
Platelet aggregation

35
Q

Role of the liver and coagulation

A

Koagulation vitamin- VIT K
Makes clotting factors
makes bile salts

36
Q

Anti-coag agents

A

warfarin and heparin

37
Q

How do heparins work

A

Activates anti thrombin 111
Inactivates thrombin and Xa

38
Q

What are the types of heparin

A

Unfractionated (inhibits thrombin and Xa)

Low molecular weight (Mainly inhibits Xa- more predictable)

39
Q

What are the advantages of Low molecular weight heparin

A

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

40
Q

How does warfarin work

A

Inhibits vitamin K reductase
Competitive
therefore Anticoagulation factors and protein C cant be made

41
Q

Does warfarin have direct action on clots?

A

No
Acts indirectly via vitamin K

42
Q

What are the pharmacokinetics of warfarin

A

Readily absorbed thru GIT
Binds to plasma proteins
Long half life! 37 hrs
Metabolised by cytochrome P450
Hard to control drug

43
Q

What is fibrinolytics

A

where clots are resolved and removed to restore blood flow
Degrades fibrin polymers into smaller products (done by plasmin)

44
Q

What is plasmin formed by and by what enzymes?

A

Plasminogen
by:
*Tissue plasmin activators (tPA)
*Urokinase Plasminogen activator (uPA)
*Kallikrein

45
Q

What drugs stimulate fibrinolysis

A

streptokinase
Urokinase- less useful/selective
Recombinant human tPA:
*reteplase
*alteplase
*tenecteplase

46
Q

What is alteplase used for

A

‘Clot selective’ as active for fibrin bound plasminogen rather than plasma bound

Acute ischaemic stroke, PVT and PE

47
Q

What 3 classes of drugs are used for angina

A

Nitrates
Beta blockers
CCBs

48
Q

What is angina pectoris

A

its a symptom
Oxygen supply to myocardium is insufficient due to partial blockage or artery spasm

49
Q

What are angina triggers

A

Increasing O2 needs and reducing O2 supply
by increasing cardiac workload or having a restricted coronary perfusion

50
Q

What decreases afterload of the heart

A

Arterial dilators- CCB and nitrates

51
Q

What decreases pre-load

A

Venodilator eg nitrates

52
Q

How to improve oxygen supply

A

CCB and nitrates
Surgery- bypass , stent etc
Decrease atherosclerosis

53
Q

What drugs are used for angina

A

Organic nitrates
CCBs
B-adrenoreceptor antagonists (slows HR)
Potassium channel activators (vasodilators)

54
Q

What are some organic nitrates and whats the MOA

A

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

55
Q

What is shear stress

A

Frictional force parallel to wall

56
Q

How do BBlockers work for angina

A

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

57
Q

What BBlocker is contraindicated for heart failure

A

Verapamil

58
Q

What do class 1 agents do and what are they

A

Na transporter blockers
can lengthen, shorten or intensify the action potential in muscle cells in ventricles

59
Q

What do class 2 agents do and what are they

A

B-Blockers
Decreases Hr, usually affects SA node
Prevents tachyarrhythmias

60
Q

What do class 3 agents do and what are they

A

Potassium Channel blockers
Widen duration of action potential
Also can use sotalol

61
Q

What do class 4 agents do and what are they

A

Calcium channel blockers
Works on AV node

62
Q

How does digoxin work

A

Inhibits Na/K ATPase
Increases Na inside myocytes/ cells
Increases exchange of Na for Ca
Increases intracellular Ca
Increases contractility of cardiac muscle

Yr 3 Cardiovascular (9 decks)

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