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Sem 5 > Pharmacology 8: Clotting therapy and Anaesthetics > Flashcards

Pharmacology 8: Clotting therapy and Anaesthetics Flashcards

1
Q

Examples of anticoagulant drugs and when are they used?

A

warfarin
heparin
tment and prophylaxis of disorders resulting from intravascular clotting- thromboembolisms.

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2
Q

synthesis of what factors related to clotting is promoted by Vit K?

A

prothrombin (II), VII, IX and X

also proteins C and S

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3
Q

what derivatives competitively antagonise

Vit K?

A

coumarin derivatives e.g. Warfarin.

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4
Q

how is warfarin therapy reversed?

A

give parenteral Vit K- slow- pro-coagulant affects re-warfarinisation for 6 weeks
fresh frozen plasma- replace activated clotting factors straight away-fast

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5
Q

ADRs of warfarin?

A 
haemorrhage
pupura
excessive bruising
nausea
hepatic dysfunction
pancreatitis
skin necrosis- more at risk if protein C or S deficient
in pregnancy- teratogen
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6
Q

active site of heparin?

A

pentasaccharide sequence- binds to Antithrombin

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7
Q

what factors does heparin inhibit?

A

thrombin, Xa (also IXa, XIa and XIIa)

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8
Q

why is heparin given IV/SC?

A

poor GI absorption- large molecular weight

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9
Q

what is dose of warfarin monitored by?

A

INR- international normalised ratio

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10
Q

what is dose of heparin monitored by?

A

APTT- activated partial thromboplastin time

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11
Q

ADRs of heparin?

A

bleeding
bruising
thrombocytopenia
osteoporosis- if LT administration

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12
Q

how can heparin therapy be reversed?

A

protamine sulphate- causes dissociation of heparin/antithrombin III complex, and binds irreversibly to heparin. Give it patient actively bleeding.

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13
Q

use of antiplatelet agents?

A

tment and prophylaxis in patients with vascular disease (mainly arterial) e.g. IHD, cerebrovascular disease.

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14
Q

examples of 2 agents which inhibit thromboxane A2?

A

aspirin

dipyridamole

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15
Q

actions of thromboxane A2?

A

platelet aggregation

vasoconstriction

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16
Q

action of dipyridamole?

A

inhibits platelet phosphodiesterase- increases cAMP which activates PKA and DECREASES intracellular Ca2+ necessary for platelet aggregation.
Positive Ionotrope and vasodilatory (flushes & headaches)
Secondary Prevention of Stroke

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17
Q

how do clopidogrel and ticlopidine inhibit platelets?

A

platelet ADP receptor antagonists- irreversibly inhibit ADP dependent pathway of platelet activation

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18
Q

why are fibrinolytic drigs which generate plasmin themselves e.g. tPA, described as clot-specific?

A

work preferentially in the presence of fibrin, in contrast to streptokinase= binds to and activates endogenous plasminogen, producing plasmin by altering its conformation, causes degree of fibrinolytic activity in general circulation.

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19
Q

why can streptokinase NOT be used twice in a patient?

A

bacterial protein (from beta-haemolytic streptococci) so antigenic, therefore on 1st use it generates blocking antibodies which persist for many yrs in patient, so would cause anaphylaxis if given again.

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20
Q

what might streptokinase cause transiently when being infused?

A

hypotension

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21
Q

contraindications for starting fibrinolytic tment after MI or PE?

A 
active peptic ulcer
recent trauma or surgery
history of cerebral haemorrhage or stroke of uncertain aetiology
uncontrolled hypertension
coagulation defect
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22
Q

when are thrombolytic/fibrinolytic drigs used?

A

STEMI- but NOT 1st line
massive PE
acute ischaemic stroke- must ensure haemorrhagic stroke eliminated as cause via CT/MRI scan*

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23
Q

symptoms and signs of acute coronary syndrome (unstable angina, STEMI/non-STEMI)?

A 
chest pain
dyspnoea
nausea
sweating
palpitations
pallor
narrow pulse pressure
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24
Q

where is plasminogen produced?

A

liver

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25
Q

what stimulate tissue plasminogen activator release in body?

A

endothelial injury

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26
Q

streptokinase t1/2?

A

15mins

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27
Q

t1/2 of alteplase (recombinat tPA)?

A

3mins

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28
Q

compare and contrast streptokinase and recombinant tPA for use in thrombolytic therapy e.g. 1st line tment in STEMI

A

-No significant difference between efficacy
-rtPAs have slightly better survival rates but higher
incidence of intracranial bleeding
-Streptokinase can only be used once (immunogenic)
-rtPAs can be used repeatedly
-rtPAs are easier to administer- rapid IV bolus injection
-rtPAs are expensive

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29
Q

how does tranexamic acid work to stop bleeding induced by thrombolytic therapy?

A

lysine analogue

binds to lysine binding sites on plasminogen and inhibits binding to fibrin and streptokinase.

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30
Q

what predicts potency for virtually all anaesthetic agents?

A

lipid solubility- to gain access to their target sites in lipid membranes

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31
Q

which anaesthetics appear to exert their primary pharmacologic action on NMDA receptors?

A

ketamine and nitrous oxide

NMDA= responsive to glutamate excitatory neurotransmitter, so inhibiton of this.

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32
Q

molecular sites of action of anaesthetics?

A

inhibitory and excitatory ligand-gated ion channels

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33
Q

how do anaesthetics affect inhibitory ligand-gated ion channels?

A

increase sensitivity of GABA and glycine activated Cl- iion channnels to hyperpolarise neurones and decrease their excitability.
Propofol- acts on GABA channels

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34
Q

excitatory ligand-gated ion channels acted upon by anaesthetics?

A

neuronal nicotinic ACh receptors- inhibition to reduce Na+ currents caused by Ach binding. Contribute to analgesia and amnesia.
NMDA receptor inhibition so reduce Ca2+ current mediated by glutamate.

35
Q

site of action of anaesthetics to cause unconsciousness?

A

thalamus

36
Q

site of action of anaesthetics to cause loss of memory?

A

hippocampus

37
Q

what is a patient on warfarin, who also enjoys binge drinking putting, putting himself at significant risk of?

A

BLEEDING, * risk of intracranial haemorrhage?: alcohol is an inhibitor of CYP450 which metabolises warfarin, so warfarin conc increased, so more likely to exert toxic ADR of bleeding
AND alcohol binge drinking may cause liver cirrhosis which will inhibit normal functioning of CYP450 and therefore again reduce metabolism of warfarin so increase risk of its ADRs.

38
Q

Major causes of hypercoagulability (factor in Virchow’s triad promoting thrombus formation)?

A

antithrombin III deficiency
Protein C or S deficiency
smoking
COCP
malignancy
nephrotic syndrome- loss of antithrombin III in urine
surgery/trauma- venous stasis, immobilisation, tissue injury.

39
Q

causes of endothelial damage?

A

hypertension
LDLs
toxins e.g. smoking
haemodynamic stress e.g. bifurcation of artery

40
Q

causes of arterial stasis?

A

AF
mitral valve disease
post MI

41
Q

causes of venous stasis?

A

post op
economy class flying
ill health causing immobility

42
Q

how is an arterial thrombus formed?

A

rupture of an atherosclerotic plaque causes platelet reactions and blood coagulation via the clotting cascade. Factor Xa activates thrombin, and thrombin causes further aggregation of platelets which secrete ADP and synthesis thromboxane A2 to cause platlet aggregation. Thrombin converts fibrinogen to fibrin, which forms the thrombus.

43
Q

how exactly does warfarin inhibit the VitK dependent synthesis of clotting factors II, VII, IX and X?

A

it acts on the carboxylation pathway, inhibiting the regeneration of reduced Vit K via competitive inhibition of epoxide reductase, so depletes reduced Vit K in liver preventing the gamma-carboxylation reaction required for clotting factor synthesis- glutamate to glutamine in prothrombin.

44
Q

why is there a delayed action in the onset of warfarin (days)?

A

as inhibits synthesis of active coagulation factors, delay represents the t1/2 of these clotting factors in the circulation.

45
Q

which pathway in the clotting cascade is impacted on most by warfarin?

A

extrinsic pathway= factor VII

pro-thrombin affected- common to both pathways, as is factor X.

46
Q

what type of molecule is heparin?

A

glycosaminoglycan- glucose backbone, acts as a cofactor to exert anticoagulant action

47
Q

which type of cell in the body releases heparin?

A

mast cells

48
Q

how does heparin deactivate clotting factors Xa and IIa (thrombin)? (though also IXa, VIIa, XIa, and XIIa)

A

antithrombin III normally binds proteases thrombin and Xa to inactivate them as they attack antithrombin III, but reaction slow without heparin- serves as a catalytic surface to which both anti-thrombin III and proteases bind, and induces a conformational change in antithrombin III that makes its reactive site more accessible to protease.
-vly charged heparin binds to +ve lysine-rich region on anti-thrombin III

49
Q

why must warfarin not be given to pregnant women?

A

teratogen- can cross placenta and cause a haemorrhagic disorder in the fetus
1st trimester= teratogenic
3rd= can cause brain haemorrhage in newborn

50
Q

PKs of warfarin?

A

ADME
good GI absorption- almost 100% oral bioavailability, certain drugs may decrease warfarin absorption e.g. cholestyramine= bile salt sequestrant
slow onset of action due to clotting factors t1/2s, so must give heparin cover= actually pro-thrombotic state of warfarin in first few days
also slow offset: t1/2 48hrs but variable, must stop 3 days before surgery.
Heavily protein bound- *DDIs e.g. with NSAIDs
Metabolised by CYP450 in liver- * caution if liver disease and use of CYP450 inhibitors e.g. alcohol, erythromycin, ciprofloxacin. Chronic heavy alcohol drinking can induce CYP450, making warfarin ineffective. Acute heavy drinking inhibits CYP450.
Excreted in urine mainly as metabolites

51
Q

how many days before surgery must warfarin be stopped due to bleeding risk in surgery?

A

3 days- gives time to synthesise

new clotting factors.

52
Q

drugs which may inhibit warfarin action?

A

CYP450 inducers- increase warfarin metabolism by CYP450 enzymes, cause decrease INR.
PCBRAS: phenytoin, carbamazepine, barbiturates, rifampicin, alcohol, St John’s Wort- used OTC in depression, and sulfonylureas.

53
Q

3 clinically significant ways in which action of warfarin is potentiated?

A
  1. CYP450 inhibitors, so inhibit hepatic metabolism e.g. alcohol, cimetidine, ciprofloxacin. ODEVICES.
  2. inhibit platelet function e.g. aspirin- PD DDI, both inhibit clotting, so increase bleeding risk.
  3. reduce Vit K from gut bacteria e.g. cephalosporin antibiotics like ceftriaxone.
    INR increase
54
Q

Main uses of warfarin?

A

DVT (3-6mnths), INR 2-3
PE (6mnths)
AF (until risk>benefit)

mechanical prosthetic valves, INR 2.5-4.5
cardiomyopathy
cerebrovascular disease with AF

55
Q

contraindications to warfarin use?

A

haemorrhagic stroke
significant bleeding
avoid use within 48hrs postpartum

56
Q

how often is INR monitored on warfarin ,and what must patient be given when started on warfarin?

A

1-4wks

given an anticoagulant card

57
Q

characteristics of low molecular weight heparins?

A

can inhibit factor Xa but not thrombin as heparin too small to bind both ATIII and thrombin, which is required for its inactivation, in contrast to only needing to bind to ATIII to inactivate factor Xa.
smaller chains
absorbed more uniformly, >90% bioavailability
long biological t1/2
more predictable does response as less binding to endothelial cells, macrophages, and plasma proteins.
can’t really monitor as only affects factor Xa
cleared by kidneys do 1/2 dose in renal failure
less likely to cause thrombocytopenia than unfractioned heparin

58
Q

why must heparin be given parenterally?

A

poor GI absorption- large and -vly charged

59
Q

compare pharmacokinetics of unfractionated and low molecular weight heparin

A

Dose-response= U= Non-linearity, L=Predictable
Bio-availability=U= Variable (unpredictable binding to
cells and proteins) L=Predictable (less
binding to macrophages and endothelium)
Action=U=Variable, Monitor with APTT test
L=No monitoring, little affect on APTT
Administration=U= IV
L=SC (Not IM!)
Initiation=U= Bolus then IV infusion
L=OD/BD- once or twice daily

60
Q

how is heparin used in thrombo-embolism prevention?

A

Peri-operative: LMWH low dose=SC
Immobility: CCF, frail or unwell patient
Used to cover for risk of thrombosis around times of
operation in those normally on warfarin but who have
stopped it for the surgery, as quick offset time allows
its cessation if bleeding.

61
Q

how is heparin used in tment?

A

DVT/PE and AF
 Administered prior to warfarin-quick onset to cover patient
whilst warfarin loading is achieved
 LMWH often used unless fine control required
 Acute Coronary Syndromes
 Reduces recurrence/extension of coronary artery thrombosis
 MI, unstable angina
 Pregnancy
 Can be used cautiously in pregnancy in place of warfarin

62
Q

how does thrombocytopenia occur with heparin and how is it treated?

A

Autoimmune phenomenon (usually 1-2 weeks of tment)
May bleed or get serious thromboses
Heparin and PF4 on platelet surface are immunogenic so once heparin bound, anitbodies generated forming immune complexes which target platelets for removal- thrombocytopenia, and activate more platelets causing aggregation, endothelial injury and thrombosis.
Platelets <100 (or a 50% reduction)
Lab assay for these antibodies
Stop heparin, add hirudin= anti-thrombotic

63
Q

despite low molecular weight heparins being preferred for routine use, why might unfractionated heparin be better in certain circumstances?

A

unfractionated heparin can be used in those at high risk of bleeding because its effect can be terminated rapidly by stopping the infusion e.g. patient in renal failure

64
Q

describe the recommended tment for DVT and PE

A

Initial treatment=a low molecular weight heparin is used; alternatively, unfractionated heparin is given as an IV loading dose (bolus), followed by continuous IV infusion (using an infusion pump) or (for deep-vein thrombosis only) by intermittent subcutaneous injection.An oral anticoagulant (usually warfarin) is started at the same time as unfractionated or low molecular weight heparin (the heparin needs to be continued for at least 5 days and until the INR is ≥2 for at least 24 hours). Monitor partial thromboplastin time (APTT) for unfractionated heparin. A low molecular weight heparin or, in some circumstances, unfractionated heparin is also used in regimens for the management of MI and unstable angina.

65
Q

What must be done 1st if haemorrhage occurs due to warfarin or heparin tment?

A

STOP DRUG!

66
Q

why might heparins be given to a mother in pregnancy?

A

Management of venous thromboembolism as don’t cross the placenta. Low molecular weight heparins are preferred because they have a lower risk of osteoporosis and of heparin-induced thrombocytopenia. Low molecular weight heparins are eliminated more rapidly in pregnancy.

67
Q

how is low molecular weight heparin given as tment in DVT and PE?

A

once or twice daily SC injection

68
Q

why are low molecular weight heparins preferred to unfractionated, espec. in prophylaxis?

A

higher therapeutic index
BUT excreted via kidneys so must be careful with use in patients with renal insufficiency.
Unfractionated excreted via reticuloendothelial system at low doses.

69
Q

how does aspirin work as an anti-platelet?

A

irreversible inhibition of COX-1 via covalent acetylation of serine, inhibiting thromboxane A2 production responsible for platelet aggregation.

70
Q

how do glycoprotein IIb and IIIa inhibitors act as anti-platelets?

A

reduce platelet crosslinking by fibrinogen as block binding of fibrinogen to receptors on platelets
e.g. abciximab- adjunct to unfractionated heparin and aspirin for the prevention of ischaemic complications in high-risk patients undergoing percutaneous transluminal coronary intervention, and in high risk acute coronary syndrome.

71
Q

why might aspirin be used as an anti-platelet drug?

A

following ischaemic stroke in ST
inital and LT tment following MI
75 mg daily in established cardiovascular disease (secondary prevention)

72
Q

why might clopidogrel be used as an anti-platelet drug?

A

Clopidogrel is licensed for the prevention of atherothrombotic events in patients with a history of symptomatic ischaemic disease. Clopidogrel, in combination with low-dose aspirin, is also licensed for acute coronary syndrome without ST-segment elevation Clopidogrel, in combination with low-dose aspirin, is also licensed for acute myocardial infarction with ST-segment elevation.
Often used with aspirin.

73
Q

general mechanism of action of thrombolytic agents?

A

convert inactive zymogen plasminogen to active protease plasmin which digests fibrin to fibrin degradation products.

74
Q

what is streptokinase used in?

A

within 12 hrs of symptom onset in acute MI

life-threatening PE

75
Q

how does streptokinase work as a thrombolytic drug?

A

binds to plasminogen, forming a stable compllex which produces a conformational change in plasminogen that exposes the protein’s proteolytically active site so that the complex can the proteolytically cleave other plasminogen molecules to plasmin.

76
Q

what is altepase (rtPA) used in?

A

between 6-12 hrs of symptom onset in acute MI
DVT and PE
acute ischaemic stroke

77
Q

why must thrombolytic drugs be avoided in severe hepatic impairment?

A

There is an increased risk of bleeding. (absence of clotting factors produced by liver)

78
Q

ADRs of thrombolytic drugs

A

Main= nausea and vomiting and bleeding.
Hypotension-can usually be controlled by elevating the patient’s legs, or by reducing the rate of infusion or stopping it temporarily.
Back pain, fever, and convulsions
Allergic reactions (including rash, flushing and uveitis) and anaphylaxis has been reported
Guillain-Barré syndrome has been reported rarely after streptokinase treatment

79
Q

why is t-PA not antigenic?

A

produced by human endothelial cells

80
Q

how does t-PA act?

A

binds to fresh thrombus, and undergoes a conformational change that allows it to activate plasminogen.
poor activator of plasminogen in absence of fibrin, so clot-specific

81
Q

indications for thrombolysis in MI?

A

If primary PCI not available/not possible < 2 hours
Chest pain onset < 12 hours (realistically < 6 hours)
ST Elevation > 2 mm in two precordial leads
> 1 mm in two limb leads
New or presumed new LBBB
No absolute contraindications
Informed consent

82
Q

absolute contraindications to thrombolytic therapy use in acute MI?

A

History of haemorrhagic stroke or stroke of unknown type
Ischaemic stroke < 6 months ago
CNS neoplasm
Gastrointestinal bleed < 1 month
Known bleeding disorder
Aortic Dissection
Major trauma/head injury/surgery < 3 weeks

83
Q

relative contraindications to thrombolysis in MI?

A 
History of TIA < 6 months
Warfarin therapy (greater risk in elderly)
Pregnancy/1 week post partum
Refractory hypertension >180 mmHg systolic
>110 mmHg diastolic
Advanced liver disease
Active peptic ulcer disease
Prolonged resuscitation

Sem 5 (35 decks)

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