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Drugs: from molecules to man > Acute Coronary Syndromes > Flashcards

Acute Coronary Syndromes Flashcards

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Organic Chemistry 101 flashcards
1
Q

What is the fundamental difference between stable angina and acute coronary syndrome?

A

in ACS blood vessels are not just partially blocked by an atherosclerotic plaque, there is also involvement of a blood clot (thrombus)

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2
Q

What are the three disorders the term ACS covers?

A

 Unstable angina
 NSTEMI: non ST (interval in ECG) elevated myocardial infarction
 STEMI: ST elevated myocardial infarction

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3
Q

What are ACS disorders characterised by?

A
  • A group of disorders characterised by severe chest pain radiating to left arm and jaw
  • Not relieved by rest – lasts more than a few minutes
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4
Q

How does an ECG help us classify what type of ACS we have?

A
  • elevation of ST interval tells us we are dealing with a STEMI (most serious)
  • ST inversion, depression or no change tells us we are probably dealing with an NSTEMI or unstable angina
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5
Q

How do you differentiate between an NSTEMI or unstable angina?

A

 You look for blood markers (proteins only present in cardiac tissues) to differentiate between NSTEMI or unstable anginas
 If you detect a blood marker it is an NSTEMI if not it is unstable angina

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6
Q

What are the different treatment methods for ACS?

A
  • reduce pain
  • reduce cardiac workload (to reduce pain caused by ischaemia)
  • prevent further thrombosis
  • reperfusion
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7
Q

What is given for pain in ACS?

A

opioids

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8
Q

What is given to reduce cardiac workload?

A

 Beta blocker: same as in stable angina (also helps overcome sympathetic nervous system activation)
 GTN (also reduces pain)

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9
Q

What is given to prevent further thrombosis?

A

 Aspirin (antiplatelet drugs)
 Ticagrelor/ clopidogrel (antiplatelet drugs)
 Heparins (anticoagulants)
 Atorvastatin (stops atherosclerosis from progressing)

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10
Q

What is given to restore blood supply?

A

 PCI
 CABG (if PCI not done straight away)
 Thrombolysis (breaking down the thrombus – drug approach)

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11
Q

What happens in haemostasis (blood clotting)?

A
  • Prevention of blood loss after vessel damage
  • Coagulation, platelet aggregation
  • Vasoconstriction
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12
Q

What are types of thrombosis and is it useful or pathological?

A
  • Pathological

- DVT (deep vein thrombosis), Embolism, Stroke, heart attack

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13
Q

What is a thrombus and what does it do?

A
  • Fibrin framework
  • Traps platelets, other blood cells
  • Attached to vessel wall
     Impedes blood flow
     Reduces perfusion of tissues
     Can cause heart attack (or stroke)
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14
Q

What has a major role in venous thrombosis?

A

Coagulation

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15
Q

What has a more important role in arterial thrombosis?

A
  • Platelet aggregation has a more important role

- Coagulation also involved

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16
Q

What may influence the drug being used in thrombosis?

A

whether it is venous or arterial

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17
Q

What is an embolus, what are the different types and what do they do?

A
  • Fragment or whole thrombus detached from vessel wall
  • Travels through vessels
  • Blocks small vessels in pulmonary, cardiac, CNS circulation
     Pulmonary embolism (from venous thrombus)
     Myocardial infarction
     Stroke
     Limb infarction
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18
Q

Why is the formation of thrombosis very serious?

A
  • Lib infarction – can lose a whole limb

- Pulmonary embolism, stroke heart attack can be fatal

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19
Q

What are the targets for modifying thrombosis processes?

A 
- Modify coagulation 
 Most successful in venous thrombosis 
- Modify platelet aggregation 
 Important in arterial thrombosis 
- Modify clot, thrombus breakdown 
 After prophylaxis fails
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20
Q

What happens in coagulation?

A
  • Proteolytic enzymes act on other modules in the cascade to convert them from the active form to the inactive form
  • IX -> IXa
  • VIIa -> VII
  • Thrombin acts of fibrinogen to turn it into fibrin
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21
Q

What are Heparins?

A
  • Family of Sulphated Mucopolysaccharides
     Have a sugar backbone and have sulphate groups attached to them
  • Repeating groups with high -ve charge (because of sulphate groups) - essential for activity
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22
Q

Where are heparins present?

A

in the liver, lungs and mast cells

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23
Q

What is the molecular weight of heparins?

A
  • Varying MW, 3-40K
     Heparin, Standard -> unfractionated – not purified, variable molecular weight
     Low MW heparins – uses purification techniques
     Enoxaparin (fondaparinux)
     Action varies between the two
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24
Q

What is thrombin, what does it do and how is it formed?

A
  • Proteolygtic enzyme
  • Cleaves soluble fibrinogen to insoluble fibrin
  • Active thrombin (IIa) is produced by cleavage of prothrombin (II) by Factor Xa
  • Factor Xa is produced from Factor X (inactive) by both Factor IXa and Factor VIIa
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25
Q

What is the action of heparin?

A
  • Inhibits action of THROMBIN, factors Xa, IXa
  • Requires presence of antithrombin III, an endogenous protease inhibitor
  • Normally ATIII opposes coagulation
  • When thrombin binds to antithrombin III it forms an inactive complex and can no longer turn fibrinogen to fibrin
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26
Q

What does unfractionated heparin do?

A
  • Quite big
  • Can bind to both Factor IIa (thrombin) and antithrombin III
  • Can bridge between the two
  • Increases the affinity of antithrombin III for factor IIa (and Xa) and increases the rate (1000 fold) of formation of anti-thrombin III-thrombin complex
  • Heparin does not bind to factor Xa but does increase ATIII/Xa complex
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27
Q

What do LMW heparins and fondaparinux do?

A
  • Shorter – can’t bridge between Factor IIa and antithrombin III
  • Increases affinity of antithrombin for factor Xa and IXa
  • Immediate action, longer lasting than heparin
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28
Q

What are some other actions of heparin?

A
  • Reduce platelet aggregation through inhibition of thrombin
  • Reduce platelet numbers
     Involves antiplatelet antibodies
  • Influence lipid metabolism
     Activates/ releases lipoprotein lipase
     Removes lipids from plasms
     People who have ACS will usually have atherosclerosis and hyperlipidaemia problems too
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29
Q

What is fondaparinux?

A
  • Synthetic sulphated muco-pentassacharide
  • Action very similar to LMW heparins (Enoxaparin)
  • Possibly has an improved side effect profile
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30
Q

What are some problems with heparin?

A
  • Poorly absorbed from oral administration
     Given Intravenously (standard – in hospital) or subcutaneously (LMW)
  • Can cause allergic reactions
  • Dose needs to be individualised to the patient
  • May need monitoring
  • Increases risk of haemorrhage because of effect of coagulation
     Mild: cease administration
     Severe: complex heparin with protamine (+ve charge)
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31
Q

What led to the formation of Warfarin?

A

• In 1920s there was some mysterious death of cattle

  • Undergo minor veterinary procedures and ended up bleeding to death
  • It was because they were eating sweet clover which had coumarin
  • If gone mouldy coumarin was converted to dicoumarol – inhibitor of clotting cascade
  • Research on dicoumarol led warfarin to be produced
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32
Q

What does Warfarin stand for and what was it first used as?

A
  • Wisconsin alumni research foundation + (coum)arin

- First used as rat poison

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33
Q

What type of anticoagulant is Warfarin?

A

Oral anticoagulant

34
Q

What is Warfarin medically used in?

A

 Venous thrombo-embolism

 Prevention of stroke in patients with atrial fibrillation; heart valve replacement

35
Q

What is Warfarin related in structure to and why?

A

related in structure to vitamin K. It antagonises vitamin K

36
Q

What does vitamin K do?

A
  • Role in formation of various clotting factors (II, VII, IX and X)
  • works in gamma carboxylation in reduced form
  • vitamin K is recycled via Vitamin K reductase
37
Q

How does Warfarin antagonise Vitamin K?

A

 Prevents y-carboxylation (leads to them being fully active) of precursors
 Precursors inactive in promoting coagulation
- Warfarin is a competitive antagonist of Vitamin K reductase so prevents Vitamin K recycling which prevents carboxylation of precursors so they are not fully active

38
Q

What are some problems with Warfarin?

A
  • slow onset
  • Actitivy influenced by amount of Vitamin K in circulation
  • Warfarin exists as R and S isomers
  • risk of haemorrhage
  • Teratogenic (should avoid in early pregnancy)
  • lots of other drug interactions
39
Q

Why is there a slow onset of Warfarin?

A

 Pre-existing factors (vitamin K and store of pre-existing clotting factors) need to be depleted
 Rate of depletion varies

40
Q

What does the amount of vitamin K in circulation depend on?

A

 Intake, absorption, gut flora

 If you kill of gut flora by having antibiotics gut flora would be reduced and Warfarin effects would be pronounced

41
Q

Is the activity of R or S Warfarin more potent and why?

A

Activity S (5x more potent), metabolic pathways differ

42
Q

If there is haemorrhage with Warfarin what do you do?

A

 Mild: stop administration

 Severe: give Vitamin K, clotting factors, whole blood

43
Q

What does Warfarin have other drug interactions through?

A

 Enzyme induction by other drugs (actions of Warfarin will be decreased)
 Enzyme inhibition by other drugs (increase amount of Warfarin in circulation)
 Displacement from protein binding (lots more in circulation and higher activity than you would need)

44
Q

Give features of newer oral drugs

A
  • Direct inhibitors of components of clotting cascade

- Easier to use as they do not require monitoring of patients like warfarin

45
Q

What is a direct inhibitor of thrombin?

A

Dabigatran

46
Q

What is a direct inhibitor of factor Xa?

A

Rivarozaban

47
Q

What is the trend in taking oral anticoagulants vs Warfarin?

A
  • Drop of Warfarin use
  • Trend of use of oral anticoagulants is upwards
  • Oral anticoagulants are replacing Warfarin in clinical use
48
Q

Are Warfarin or oral anticoagulants easier to use and which has better outcomes?

A

Oral anticoagulants are easier to use and have better outcomes

49
Q

What is the controversy about Dabigatran?

A
  • Marketed by suggesting that it wouldn’t need monitoring unlike Warfarin
  • Boehringer Ingelheim withheld information about monitoring: if you conduct monitoring it is even better
50
Q

What is hirudin?

A

a peptide that is a competitive inhibitor of thrombin and cannot be administered orally because it is broken down in the GI tract

51
Q

What is Bivalirudin?

A

is a synthetic hirudin analogue that is a competitive substrate at thrombin

52
Q

What does damage to a blood vessel lead to?

A
  • Platelet adhesion, activation and aggregation

- This leads to a thrombus

53
Q

What are platelets?

A
  • Derived from megakaryocytes (bone marrow cells)
  • Fragments of cytoplasm (no nucleus)
  • Platelets have glycoprotein receptors which interact with collagen and other glycoproteins triggering the activation of platelets
54
Q

What are the stages of platelet aggregation and activation?

A
  1. Platelets adhere to collagen and other glycoproteins through glycoprotein receptors
  2. Triggers platelets to activate
  3. Triggers dramatic change in shape (becomes star shaped)
  4. Releases signalling molecules: TXAs and ADP which are released into the blood and will activate other platelets
  5. Expression of different type of glycoprotein receptor on platelet membrane
55
Q

What is the stimuli for platelet aggregation/activation?

A

 Thrombin
 ADP
 TxA2

56
Q

What is TxA2 synthesised from?

A
  • TxA2 synthesised from arachidonic acid by cyclo-oxygenase (COX)
  • Platelets synthesise TxA2 when activated
57
Q

What dies TxA2 do?

A

 Enhances expression of glycoprotein IIb/IIIa receptors
 These receptors bind fibrinogen
 Receptors on membranes of adjacent platelets bind the same fibrinogen molecule -> this leads to platelets linking together becoming aggregated
 Then a chain reaction occurs

58
Q

What stops the aggregation chain reaction from spreading?

A
  • Prostacyclin released from intact epithelium
  • Has opposite effect of TxA2
  • Inhibits platelet activation
59
Q

How are prostacyclin (PGI2) and Thromboxane (TXA2) derived?

A
  • Prostacyclin (PGI2) and Thromboxane (TXA2) derive from same place
     Membrane phospholipids ->
     Arachidonic acid (+ COX enzyme) ->
     PG endoperoxides ->
     PGE2 + synthetase enzymes (thromboxane)
     Thromboxane increases platelet aggregation by decreasing cAMP
     OR
     PGE2 ->
     Prostacyclin, PGI2
     PGI2 decreases platelet aggregation by increasing cAMP
60
Q

What are the three COX genes humans have?

A
  • COX1 is a ‘housekeeping’ gene expressed in most cells and involved in the synthesis of thromboxane A2 and prostacyclin
  • COX2 is expressed mainly in inflamed tissues and it the target of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and aspirin
  • COX3 gene in humans has a frameshift mutation and so does not produce active enzyme
61
Q

Despite producing their anti-inflammatory effects at COX2 why do many of them produce side effects such as worsening GI tract ulcers?

A

most of them also have actions at COX1 and it is these COX1 effects that produce many of the side effects of NSAIDs, e.g. worsening GI tract ulcers

62
Q

What are ‘coxibs’, why were they formed and why have they been withdrawn from the market?

A
  • ‘coxibs’ were synthesised in the late 1990s and initially enjoyed great success as analgesics and anti-inflammatory drugs because they avoided the GI tract problems of non-selective drugs
    • However, post-marker surveillance of the safety of coxibs revealed that patients that were taking them had a higher rate of serious CVS problems than the general population and now most of the coxibs have been withdrawn from the market
63
Q

What does aspirin do?

A
  • Irreversibly blocks platelet COX enzyme, reducing TxA2 synthesis
  • Low doses of aspirin used to avoid reducing enzyme in endothelium (source of prostacyclin)
  • Aspirin alters balance between platelet TxA2 and endothelial prostacyclin (PGI2)
  • Aspirins work because if we irreversibly inhibit COX in platelets then they won’t be able to make any more enzyme
  • If we inhibit the COX in endothelial cells they can replace their enzyme and maintain prostacyclin production.
  • This is how we use a molecule that has two different effects on signalling molecules
64
Q

What are the unwanted effects of aspirin?

A
  • Extended bleeding time
  • Indigestion
  • Allergy (rare)
  • May provoke asthma attacks (involved diverting membrane derived recodonic acid into pro-inflammatory signalling molecules)
  • Reye’s syndrome (under 16s) – liver and brain damage. Aspirin use during viral illness
65
Q

What do antiplatelet drugs have action through?

A

action via modulating expression of glycoprotein IIb/IIIa receptors

66
Q

What does Clopidogrel do?

A
  • Clopidogrel inhibits glycoprotein IIb/IIIa receptor expression on platelets by blocking the ADP receptor irreversibly
     Not used so much in the clinic
67
Q

What does Ticagrelor do?

A

allosterically inhibits the ADP receptor (reversible)

68
Q

What happened in the PLATO trial?

A
  • Compared clopidogrel with ticagrelor
  • Ticagrelor shown to have 16% lower mortality
  • Clopidogrel is a prodrug: requires CYP2C19 enzyme to be activated
  • About 30% of people have low functioning CYP2C19 alleles – clopidogrel much less effective in these people
  • Was difference between drugs due to genetic non-responders?
  • No…genetic sub-study shows that ticagrelor is still superior
69
Q

What are the unwanted effects of Clopidogrel and ticagrelor?

A
  • Extended bleeding time
  • GI tract problems (nausea, indigestion etc)
  • Headaches, dizziness
  • Gout (ticagrelor)
  • Breathlessness (ticagrelor)
70
Q

What do antiplatelet drugs do?

A

Raise cAMP levels and prevent aggregation

71
Q

What does Dipyridamole do?

A

 Phosphodiesterase (PDE3) inhibitor (this enzyme breaks cAMP down into an inactive form)
 Prevents the breakdown of cAMP in platelets
 cAMP reduces platelet aggregation

72
Q

What are the unwanted effects of Dipyridamole?

A
  • GI tract problems (nausea, indigestion etc.)
  • Headaches, dizziness
  • Muscle pain
  • Flushing/ feeling hot (vasodilator)
  • Can precipitate/ worsen angina
73
Q

What is Coronary Steal?

A
  • If given GTN we see flow via collateral vessels increased which increases blood flow to ischaemic tissue and dilation of capacitance vessels
  • With dipyridamole we see healthy vessels dilated but no dilation of collateral vessel. Because blood vessel with atherosclerotic plaque has higher resistance than healthy vessels, healthy vessels will divert blood flow away from collateral vessel – coronary steal
74
Q

What does plasmin do and how is it formed?

A
  • Attacks fibrin and breaks it down to fibrin degradation products
  • In circulation it is the inactive precursor plasminogen
  • Plasminogen must be cleaved by tissue plasminogen activator to produce plasmin
75
Q

How do all thrombolytic drugs work?

A

By supplementing tissue plasminogen activator?

76
Q

Give examples of thrombolytic drugs

A
  • Reteplase (mutated version of tissue plasminogen activator)
  • Alteplase
  • Streptokinase – first thrombolytic drug. Not used much in US and UK – replaced by reteplase and alteplase
  • Reteplase and Alteplase have very close structure to tissue plasminogen activator
77
Q

In what time frame do thrombolytic drugs work and why?

A
  • Drugs work if given quickly – they dissolve clots
  • If clots are allowed to sit it changes it’s structure and becomes resistant to the thrombolytics. This means if used in treating stroke of heart attack we only have a four and a half hour window to use it
78
Q

What is the main method for reperfusion of cardiac tissue in the UK?

A

PCI

79
Q

Give features of PCI

A
  • Rapid
  • Relatively safe
  • Requires specialist centre
  • Over last 20 years number of specialist centres offering PCI has dramatically increased so easier to get patients to there
  • This is why PCI has largely replaced thrombolysis in initial stages of heart attack treatment
80
Q

Give features of thrombolysis

A
  • Very rapid
  • Relatively risky (risk of haemorrhage)
  • Requires little equipment (just given through IV)
  • Used to be used extensively

Drugs: from molecules to man (22 decks)

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