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Exam prep tutorials (Pharmacology) > Drugs acting in the bloodstream > Flashcards

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.

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2
Q

Where is tissue factor present?

A
  • injured endothelium
  • tissue factor bearing fibroblasts and monocytes
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3
Q

Summary of the Intrinsic and Extrinsic Coagulation Cascade

A
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4
Q

What happens in initiation of coagulation?

A

Results in formation of prothombinase.

Factor VII and tissue factor play a key role.

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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.

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6
Q

What is propagation in coagulation?

A

Massive thrombin burst.

This thrombin converts fibrinogen to fibrin resulting in a stable fibrin clot.

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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
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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

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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.

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10
Q

What does factor Xa do?

A

The Factor Xa/VIIa/TF complex activates factor V

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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)

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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
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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
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14
Q

What is the structure of warfarin?

A

A coumarin derivative found in plants (lavender and woodruff)

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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
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16
Q

How plasma protein bound is warfarin?

A

99%

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17
Q

Where is warfarin metabolised and where is it excreted?

A

Metabolized entirely by liver.

Metabolites excreted in urine and faeces.

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18
Q

What is the half life of warfarin?

A

35 - 45 hrs

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19
Q

What drugs does warfarin inhibit metabolism of?

A
  • cimetidine
  • alcohol
  • allopurinol
  • erythromycin
  • ciprofloxacin
  • metronidazole
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20
Q

What drugs does warfarin displace from plasma proteins?

A
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21
Q

What drugs does warfarin induce enzymes for?

A
  • barbiturates
  • rifampicin
  • carbamazepine
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22
Q

What does warfarin do to fat soluble vitamin absorption?

A

It causes decreased fat soluble vitamin absorption.

So inhibits cholestyramine.

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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)

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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
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25
Q

How do you treat warfarin overdose or a high INR for major bleeding?

A
  • 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)
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26
Q

What are the risks of warfarin in pregnancy?

A
  • 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)
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27
Q

What is the alternative to warfarin for pregnant people?

A

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.

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28
Q

What is heparin?

A
  • 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
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29
Q

What is the MOA of heparin?

A
  • 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
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30
Q

What are the pharmacokinetics of unfractionated heparin?

A
  • 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
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31
Q

What are LMWHs?

A
  • 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
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32
Q

What are the advantages of LMWH?

A
  • 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
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33
Q

What are the most common adverse reactions to heparin?

A
  • haemorrhage
  • hyperkalaemia
  • hypotension
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34
Q

What is heparin induced thrombocytopenia (HIT)?

A
  • 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%
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35
Q

What is danaparoid?

A
  • 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
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36
Q

What are the adverse effects of danaparoid?

A
  • low platelets
  • due to a low level of structural similarity between danaparoid and heparin
  • exacerbation of asthma
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37
Q

What is fondaparinux?

A
  • 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
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38
Q

What is rivaroxaban?

A
  • 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
Q

Does heparin have direct antiplatelet activity?

A

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
Q

What does protamine do?

A

It partially reverses LMWH.
Only anti-IIa activity is fully reversed, anti-Xa activity is partially reversed.

41
Q

Why is heparin-induced thrombocytopenia not dose-dependent?

A

It can occur after the first dose of heparin

42
Q

What do amiodarone, gliclazide and metronidazole do to a patient’s INR?

A

They all increase INR.

Gliclazide and amiodarone displace warfarin from albumin. Metronidazole is an enzyme inhibitor reducing warfarin metabolism.

43
Q

How does the effect of unfractionated heparin on platelets compare to LMWHs effect?

A

LMWH interacts less with platelets

44
Q

How long should elapse after LMWH before attempting central neuraxial block?

A

At least 12hrs.

Anti-Xa activity is about 50% of peak 12hrs after dosing.

45
Q

How soon after an uneventful spinal/epidural can LMWH be given?

A

2hrs

46
Q

What does stopping aspirin do to the risk of death?

A

Doubles it

47
Q

What does the GPIIb/IIIa receptor do?

A

Binds to fibrinogen (adhesion) and platelet aggregation.

It is activated by thomboxane A2 and ADP.

48
Q

Where is thromboxane A2 produced?

A

From the arachidonic acid pathway inside the platelet. This pathway is initiated by platelet activation.

TXA2 also aids haemostasis through vasoconstricting effects.

49
Q

What does ADP do to the GPIIb/IIIa receptor?

A

ADP is secreted by activated platelets and binds to adjacent platelet receptors and activates GPIIb/IIIa receptor through a common pathway.

50
Q

How does aspirin work?

A

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
Q

What is the MOA of clopidogrel?

A

Blocks the ADP-induced platelet activation pathway. Prevents ADP from activating the common pathway.

52
Q

What do GPIIb/IIIa antagonists do?

A

Block the GPIIb/IIIa receptor. This prevents the binding of receptor to fibrinogen and platelet adherence is inhibited.

53
Q

What is COX1 and COX2?

A

COX1 plays a homeostatic role.

COX2 is inducible and produced in response to tissue injury facilitating the inflammatory response.

54
Q

What does thromboxane A2 do?

A

Plays a key role in strengthening the clot through binding fibrinogen

55
Q

Which COX isoenzyme does aspirin affect?

A

Aspirin is 50-100x more effective against COX1 than 2, thus larger doses are required to achieve anti-inflammatory effects.

56
Q

What is normal platelet turnover?

A

10% per day

57
Q

How long does it take for platelets to return to normal after aspirin treatment?

A

7-10 days

58
Q

What is the pKa of aspirin and is it an acid/base?

A

It’s a weak acid.

pKa 3

59
Q

Why is aspirin well absorbed orally?

A

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
Q

How plasma protein bound is aspirin?

A

85% (mainly to albumin)

61
Q

What is the half life of aspirin?

A

15-20 mins

62
Q

What is aspirin hydrolyzed to?

A

Acetic acid and salicylate.

Converted to H2O soluble products in the liver, and excreted by kidneys.

63
Q

How effective is aspirin at reducing cardiovascular mortality?

A
  • 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
Q

What is the mortality rate of an acute overdose of aspirin?

A

2%

65
Q

What would an ABG of someone with an aspirin OD show?

A
  • 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
Q

What are the clinical signs of an aspirin OD?

A
  • tachycardia
  • pyrexia
  • sweaty
  • blurred vision
  • hyperventilation
  • tinnitus
  • usually conscious
67
Q

What is the treatment for aspirin overdose?

A
  • 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
Q

What counts as a severe aspirin overdose requiring haemodialysis?

A
  • Significantly high salicylate blood levels >100 mg/dL
  • Significant neurotoxicity
  • Renal failure
  • Pulmonary oedema
  • Cardiovascular instability
69
Q

What is the chemical structure of clopidogrel?

A

Thienopyridine derivative

70
Q

How does clopidogrel work?

A
  • 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
Q

What is the half life of clopidogrel?

A

It is rapidly absorbed and extensively metabolized with an elimination t1/2 of about 8 hours

72
Q

What is clopidogrel used for?

A
  • 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
Q

How effective is clopidogrel in reducing ischaemic complications?

A
  • at least as effective as aspirin
  • CAPRIE trial showed a relative risk reduction of 8.7%, p = 0.043 of clopidogrel over aspirin
74
Q

What are possible SEs of clopidogrel?

A
  • haemorrhage (GI 2%, cerebral 0.1 - 0.4% annually)
  • thrombocytopenia
  • ticlodipine (same family as clopidogrel) may cause aplastic anaemia
75
Q

At what dose of clopidogrel does maximal platelet inhibition occur?

A

With a loading dose of 400mg.

This can be fully reversed with a platelet infusion.

76
Q

What is dual therapy (aspirin + clopidogrel) recommended for?

A
  • 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
Q

Why can aspirin and clopidogrel cause severe intraoperative haemorrhage/haematoma?

A

They work synergistically

78
Q

What is GPIIb/IIIa?

A

It’s the “hook” expressed on the platelet that allows it to adhere to fibrinogen or other platelets.

79
Q

What are GP IIb/IIIa antagonists used for?

A

In management of acute coronary syndrome and PCI.

They occur as monoclonal antibodies to the receptor (eg abciximab)

80
Q

How long are the effects of GP IIb/IIa antagonists seen for after cessation of treatment?

A

Up to 48hrs. This is due to high affinity of the drug for the receptors.

81
Q

What SEs can GPIIb/IIIa antagonists have?

A
  • thrombocytopenia
  • increased bleeding perioperatively
    • requires a platelet transfusion
82
Q

What is the MOA of GPIIb/IIIa antagonists?

A
  • 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
Q

What is dipyridamole?

A

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
Q

What is the terminal half life of dipyridamole?

A

10 hours

85
Q

What is the MOA of dipyridamole?

A
  • as a phosphodiesterase inhibitor it potentiates the action of prostacyclin
  • directly stimulates release of prostacyclin
  • inhibits metabolism of adenosine
86
Q

What is dipyridamole used for?

A

An additive effect to aspirin in secondary prevention with ischaemic stroke or TIA (for 2 years).

Limited use because of 25% headache incidence.

87
Q

What receptor does clopidogrel block?

A

P2Y12ADP receptor

88
Q

Can aspirin overdose cause coma?

A

Only in massive OD

89
Q

What is a human-murine monoclonal antibody?

A

Abciximab (GPIIb/IIIa inhibitor)

90
Q

How long after abciximab does platelet aggregation return to normal?

A

96 to 120 hrs after the drug is stopped

91
Q

What must the receptor occupancy be of abciximab for bleeding time to be severely prolonged?

A

more than 90%

92
Q

What is the dose of abciximab?

A

0.25 mg/kg bolus followed by a 12hr infusion.

Plasma half life is only 10minutes.

93
Q
A

Exam prep tutorials (Pharmacology) (8 decks)

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