Drugs acting in the bloodstream Flashcards
1
Q
What is the purpose of the endothelial cells lining the vascular space?
A
They provide a non-thrombogenic surface preventing unnucessary coagulation, thrombosis and platelet activation.
If disrupted, platelets are exposed to extravascular tissue and become partially activated by tissue factor.
2
Q
Where is tissue factor present?
A
- injured endothelium
- tissue factor bearing fibroblasts and monocytes
3
Q
Summary of the Intrinsic and Extrinsic Coagulation Cascade
A
4
Q
What happens in initiation of coagulation?
A
Results in formation of prothombinase.
Factor VII and tissue factor play a key role.
5
Q
What happens in amplification of coagulation?
A
Platelets are activated. The platelet is activated by various coagulation factors of which thrombin (factor IIa) plays a key role.
6
Q
What is propagation in coagulation?
A
Massive thrombin burst.
This thrombin converts fibrinogen to fibrin resulting in a stable fibrin clot.
7
Q
What happens when extravascular tissue is damaged?
A
- bares tissue factor
- this TF partially activates platelets
- this results in
- expression of platelet gylcoprotein 1b/factor IX
- release of VWF that attaches platelet to subendothelial collagen
- externalization of plasma membrane phosphatidylserines that provides scaffold for coagulation complexes
8
Q
What does factor VII do?
A
Circulating factor VII attaches to TF that is present on the damaged endothelium and fibroblasts/monocytes that have migrated to the site of injury
9
Q
What does factor VIIa/TF complex do?
A
Activates factors IX and X
Factor IXa migrates to the platelet surface.
Factor Xa forms a complex with VIIa/TF.
10
Q
What does factor Xa do?
A
The Factor Xa/VIIa/TF complex activates factor V
11
Q
What does Factor Xa/Va do?
A
Factor Xa separates from its parent complex and joins factor Va to become Xa/Va, also known as prothrombinase
The remaining VIIa/TF is inactivated by Tissue Factor Pathway Inhibitors (TFPI)
12
Q
What happens after initiation?
A
Amplification - occurs on surface of the platelets
- The prothrombinase converts prothrombin into small amounts of thrombin (factor IIa)
- This thrombin activates factors V, VIII, X and XI
- These factors fully activate the platelet
- Thrombin also has some direct activating effect
13
Q
What stage comes after amplification?
A
Propagation - occurs on surface of activated platelets
- the activated platelet expresses prothrombinase (factor Va/Xa complex) and tenase (factor VIIIa/IXa complex) on the surface
- these complexes cause a massive conversion of prothrombin into thrombin, known as a ‘thrombin burst’. One prothromibinase complex can generate 1000 molecules of thrombin
- this thrombin converts fibrinogen into fibrin that forms the stable haemostatic clot
14
Q
What is the structure of warfarin?
A
A coumarin derivative found in plants (lavender and woodruff)
15
Q
What is the action of warfarin?
A
- inhibits vit K dependent coagulation factors
- 2, 7, 9, 10
- protein C and S also inhibited
- production of clotting factors is dependent on carboxylation of precursor proteins
- during this reaction vit K is oxidized to vit K epoxide, an inactive form
- warfarin inhibits the enzyme (vit K epoxide reductase) responsible for reducing it back to vit K
16
Q
How plasma protein bound is warfarin?
A
99%
17
Q
Where is warfarin metabolised and where is it excreted?
A
Metabolized entirely by liver.
Metabolites excreted in urine and faeces.
18
Q
What is the half life of warfarin?
A
35 - 45 hrs
19
Q
What drugs does warfarin inhibit metabolism of?
A
- cimetidine
- alcohol
- allopurinol
- erythromycin
- ciprofloxacin
- metronidazole
20
Q
What drugs does warfarin displace from plasma proteins?
A
21
Q
What drugs does warfarin induce enzymes for?
A
- barbiturates
- rifampicin
- carbamazepine
22
Q
What does warfarin do to fat soluble vitamin absorption?
A
It causes decreased fat soluble vitamin absorption.
So inhibits cholestyramine.
23
Q
How many days does prothrombin levels take to decrease by 50% when starting warfarin?
A
3 days (although shorter if patient is unwell or if there are drug interactions)
24
Q
How is warfarin monitored?
A
- by a single point prothrombin time, sensitive to factors 2, 7 and 10
- the INR is a ratio of the patient’s prothrombin time to a normal (control) sample
25
How do you treat warfarin overdose or a high INR for major bleeding?
* stop warfarin
* give **15mls/kg of FFP**
* this doesn't fully reverse the effects (factor 9 does not rise \>20% post FFP)
* give **Vit K 5mg**
* 1mg reverses effects within 12hrs
* 10mg will saturate liver stores preventing re-warfarinisation
* **Prothrombin complex concentrate 30-50 Units/kg** can be used for complete reversal
* *if minor/no bleeding, only Rx INR if \>8 plus risk factors (eg HTN or previous GI bleed)*
26
What are the risks of warfarin in pregnancy?
* crosses the placenta and can cause fetal haemorrhage
* associated with spontaneous abortion
* stillbirth
* neonatal death
* preterm birth
* teratogen with a 5% incidence of birth defects (worst in 1st trimester)
27
What is the alternative to warfarin for pregnant people?
LMWH - as it does not cross the placenta and doesn't cause birth defects
However, risk of maternal haemorrhage with heparin use is high and preterm or stillbirth may still occur.
28
What is heparin?
* glycosaminoglycan which is a mucopolysaccharide
* it is an organic acid
* occurs naturally in liver and mast cells
* derived from porcine intestinal mucosa
* molecular weight is 12 - 15 kDa
29
What is the MOA of heparin?
* binds reversibly and potentiates antithrombin III, a plasma serine protease inhibitor
* ATIII mainly inhibits coagulation factors 2, 4 and 10
* also inhibits factors 12, 11 and plasmin
* it's antiplatelet effects are mediated through it's effects on fibrin
30
What are the pharmacokinetics of unfractionated heparin?
* given SC or IV
* not absorbed orally due to size and negative charge
* highly plasma protein bound (to fibrinogen and albumin)
* low lipid solubility and does not cross BBB/placenta
* half life 30-60mins
* metabolized by hepatic heparinase
* excreted in urine
31
What are LMWHs?
* short chain polysaccharides with a predictable anticoagulant action
* average molecular weight \<8000 Da
* produced by depolymerization or fractionation of heparin
* has full anti-Xa action but less anti-IIa action due to shorter chain lengths
* the half life of most LMWHs are 2-3 times longer than unfractionated heparin (because they have a lower affinity for heparin-binding proteins)
* can be monitored by factor Xa assays
32
What are the advantages of LMWH?
* Once daily dosing
* No need for APTT monitoring
* Possibly a smaller risk of bleeding as it interacts less with platelets
* Smaller risk of osteoporosis in long-term use
* Smaller risk of heparin-induced thrombocytopenia
* Has less of an effect on thrombin compared to heparin, but maintains the same effect on Factor Xa
33
What are the most common adverse reactions to heparin?
* haemorrhage
* hyperkalaemia
* hypotension
34
What is heparin induced thrombocytopenia (HIT)?
* immune mediated thrombocytopaenia where heparin sulphate is recognised as foreign
* heparin binds to platelet factor IV stimulating IgG antibody formation which predisposes to thrombosis
* most are asymptomatic
* typically platelet count falls 5-14 days after heparin is started (can start in 24h if theyve had heparin in last 3 months)
* incident 3%
35
What is danaparoid?
* can be used in patient with HIT
* factor Xa inhibitor
* heparinoid similar to LMWH
* consists of mix of heparan sulfate, dermatan sulfate and chonroitin sulfate
* IV or SC administration
36
What are the adverse effects of danaparoid?
* low platelets
* due to a low level of structural similarity between danaparoid and heparin
* exacerbation of asthma
37
What is fondaparinux?
* Synthetic pentasaccharide similar to heparin
* Factor Xa inhibition
* Administer subcutaneously once daily and does not need therapeutic monitoring
* Plasma t½ is 21 h and renally excreted. Avoid in renal failure
* Used for thromoboprophylaxis in major joint replacement surgery
* Risk of HIT is substantially lower. Used in patients with established HIT as it has no affinity for PF-4
* Shown to reduce major bleeding and improve long term morbidity and mortality
38
What is rivaroxaban?
* Similar to an oral heparin
* Factor Xa inhibition
* Once daily dosing orally
* Does not need therapeutic monitoring
* Used in thromboprophylaxis in major joint replacement surgery
39
Does heparin have direct antiplatelet activity?
No, it affects the coagulation pathway mainly by binding to AT III and it's antiplatelet effects are mediated through it's effects on fibrin
40
What does protamine do?
It partially reverses LMWH.
Only anti-IIa activity is fully reversed, anti-Xa activity is partially reversed.
41
Why is heparin-induced thrombocytopenia not dose-dependent?
It can occur after the first dose of heparin
42
What do amiodarone, gliclazide and metronidazole do to a patient's INR?
They all increase INR.
Gliclazide and amiodarone displace warfarin from albumin. Metronidazole is an enzyme inhibitor reducing warfarin metabolism.
43
How does the effect of unfractionated heparin on platelets compare to LMWHs effect?
LMWH interacts less with platelets
44
How long should elapse after LMWH before attempting central neuraxial block?
At least 12hrs.
Anti-Xa activity is about 50% of peak 12hrs after dosing.
45
How soon after an uneventful spinal/epidural can LMWH be given?
2hrs
46
What does stopping aspirin do to the risk of death?
Doubles it
47
What does the GPIIb/IIIa receptor do?
Binds to fibrinogen (adhesion) and platelet aggregation.
It is activated by thomboxane A2 and ADP.
48
Where is thromboxane A2 produced?
From the arachidonic acid pathway inside the platelet. This pathway is initiated by platelet activation.
TXA2 also aids haemostasis through vasoconstricting effects.
49
What does ADP do to the GPIIb/IIIa receptor?
ADP is secreted by activated platelets and binds to adjacent platelet receptors and activates GPIIb/IIIa receptor through a common pathway.
50
How does aspirin work?
Inhibits COX enzymes within the platelet, preventing production of prostaglandins and thromboxanes by the activated platelet.
The formation of thromboxane A2 is prevented and this results in a reduction in GP IIb/IIIa receptor activation and vasoconstriction.
51
What is the MOA of clopidogrel?
Blocks the ADP-induced platelet activation pathway. Prevents ADP from activating the common pathway.
52
What do GPIIb/IIIa antagonists do?
Block the GPIIb/IIIa receptor. This prevents the binding of receptor to fibrinogen and platelet adherence is inhibited.
53
What is COX1 and COX2?
COX1 plays a homeostatic role.
COX2 is inducible and produced in response to tissue injury facilitating the inflammatory response.
54
What does thromboxane A2 do?
Plays a key role in strengthening the clot through binding fibrinogen
55
Which COX isoenzyme does aspirin affect?
Aspirin is 50-100x more effective against COX1 than 2, thus larger doses are required to achieve anti-inflammatory effects.
56
What is normal platelet turnover?
10% per day
57
How long does it take for platelets to return to normal after aspirin treatment?
7-10 days
58
What is the pKa of aspirin and is it an acid/base?
It's a weak acid.
pKa 3
59
Why is aspirin well absorbed orally?
The acidic pH of the stomach keeps a large fraction unionized, so it's readily absorbed.
But the small intestine has a larger surface area, so a greater amount is absorbed here.
60
How plasma protein bound is aspirin?
85% (mainly to albumin)
61
What is the half life of aspirin?
15-20 mins
62
What is aspirin hydrolyzed to?
Acetic acid and salicylate.
Converted to H2O soluble products in the liver, and excreted by kidneys.
63
How effective is aspirin at reducing cardiovascular mortality?
* in those with high risk vaso-occlusive disease, aspirin reduced non-fatal MI by about 1/3
* in non-fatal stroke and vascular death the reduction was 15%
* there is however, a 1-2% incidence of major GI haemorrhage on aspirin therapy
64
What is the mortality rate of an acute overdose of aspirin?
2%
65
What would an ABG of someone with an aspirin OD show?
* mixed acid-base picture
* aspirin uncouples oxidative phosphorylation - increases O2 consumption and CO2 production
* initially minute ventilation increases to keep PaCO2 static, ventilation is further increased by direct stimulation of the respiratory centre resulting in resp alkalosis
* impaired aerobic metabolism results in metabolic acidosis
66
What are the clinical signs of an aspirin OD?
* tachycardia
* pyrexia
* sweaty
* blurred vision
* hyperventilation
* tinnitus
* usually conscious
67
What is the treatment for aspirin overdose?
* activated charcoal absorbs aspirin in the GI tract
* IV fluid resus to maintain urine output between 1-2 mls/kg/h
* alkalinization of urine with sodium bicarbonate in significant OD (salicylate level \>35 mg/dl, 6hrs after ingestion) - enhances removal of salicylate from blood
* haemodialysis in severely poisoned patients
68
What counts as a severe aspirin overdose requiring haemodialysis?
* Significantly high salicylate blood levels \>100 mg/dL
* Significant neurotoxicity
* Renal failure
* Pulmonary oedema
* Cardiovascular instability
69
What is the chemical structure of clopidogrel?
Thienopyridine derivative
70
How does clopidogrel work?
* thienopyridine derivative
* blocks ADP-induced platelet activation pathway (P2Y12ADP)
* It prevents platelet activation caused by shear stress after acute vessel injury
* It has irreversible platelet effects and should be stopped seven days pre-surgery
* It is a prodrug activated by oxidation of the thiophene ring by cP450
71
What is the half life of clopidogrel?
It is rapidly absorbed and extensively metabolized with an elimination t1/2 of about 8 hours
72
What is clopidogrel used for?
* Acute coronary syndrome/ NSTEMI for 9-12 months post event
* STEMI, for 1 month post event
* Prevention of thrombosis post coronary stent placement
* Prevention of vascular ischaemic events in patients with symptomatic atherosclerosis
73
How effective is clopidogrel in reducing ischaemic complications?
* at least as effective as aspirin
* CAPRIE trial showed a relative risk reduction of 8.7%, p = 0.043 of clopidogrel over aspirin
74
What are possible SEs of clopidogrel?
* haemorrhage (GI 2%, cerebral 0.1 - 0.4% annually)
* thrombocytopenia
* ticlodipine (same family as clopidogrel) may cause aplastic anaemia
75
At what dose of clopidogrel does maximal platelet inhibition occur?
With a loading dose of 400mg.
This can be fully reversed with a platelet infusion.
76
What is dual therapy (aspirin + clopidogrel) recommended for?
* NSTEMI (for 9-12 months)
* stable CAD at high risk of MI (taken lifelong)
* PCI with stents
* aspirin lifelong
* stable angina: dual therapy for 4 weeks with BMS
* 6 -12 months with drug eluting stents
* post STEMI/nSTEMI
* dual therapy 12 months
77
Why can aspirin and clopidogrel cause severe intraoperative haemorrhage/haematoma?
They work synergistically
78
What is GPIIb/IIIa?
It's the "hook" expressed on the platelet that allows it to adhere to fibrinogen or other platelets.
79
What are GP IIb/IIIa antagonists used for?
In management of acute coronary syndrome and PCI.
They occur as monoclonal antibodies to the receptor (eg abciximab)
80
How long are the effects of GP IIb/IIa antagonists seen for after cessation of treatment?
Up to 48hrs. This is due to high affinity of the drug for the receptors.
81
What SEs can GPIIb/IIIa antagonists have?
* thrombocytopenia
* increased bleeding perioperatively
* requires a platelet transfusion
82
What is the MOA of GPIIb/IIIa antagonists?
* block the final common pathway preventing the binding of fibrinogen
* reduce platelet activity, thrombin effects and neointima formation in damaged arteries
* reduce platelet aggregation at 50% receptor occupation and almost completely abolish aggregation at 80% occupancy
83
What is dipyridamole?
Pyrimidopyrimidine derivative (phosphodiesterase inhibitor) which has:
* antiplatelet effect - inhibits platelet adhesion to the vessel wall
* vasodilating effects - particularly affects coronary artery
* is excreted by the biliary tree and is subject to enterohepatic circulation
84
What is the terminal half life of dipyridamole?
10 hours
85
What is the MOA of dipyridamole?
* as a phosphodiesterase inhibitor it potentiates the action of prostacyclin
* directly stimulates release of prostacyclin
* inhibits metabolism of adenosine
86
What is dipyridamole used for?
An additive effect to aspirin in secondary prevention with ischaemic stroke or TIA (for 2 years).
Limited use because of 25% headache incidence.
87
What receptor does clopidogrel block?
P2Y12ADP receptor
88
Can aspirin overdose cause coma?
Only in massive OD
89
What is a human-murine monoclonal antibody?
Abciximab (GPIIb/IIIa inhibitor)
90
How long after abciximab does platelet aggregation return to normal?
96 to 120 hrs after the drug is stopped
91
What must the receptor occupancy be of abciximab for bleeding time to be severely prolonged?
more than 90%
92
What is the dose of abciximab?
0.25 mg/kg bolus followed by a 12hr infusion.
Plasma half life is only 10minutes.
93
