Session 12 Flashcards

1
Q

Describe bacterial structure

A

• DNA present in nuclei and

plasmids • Cell membrane and wall • Other specialised features

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2
Q

how anti-microbials work Mechanisms

A
  • 5 main methods
  • Inhibiting cell wall synthesis
  • Inhibiting nucleic acid synthesis
  • Stopping metabolite production
  • Inhibiting cell membrane synthesis
  • Inhibiting protein synthesis
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3
Q

What’s the difference between bactercidal and bacteriostatic?

A
• Bactericidal – means destroying, or
killing bacteria. • Bacteriostatic – stopping divisions
and replication of bacteria, slowing
the growth. The bacteria are still alive
and rely on body’s usual mechanisms
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4
Q

Classes of antibiotic

A

Insert table

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5
Q

Antibiotic resistance

A
  • Example
  • Beta lactamase enzymes
  • Efflux pumps • Plasmid DNA can be passed from cell to cell
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6
Q

• Why do we need to monitor?

A
• Narrow therapeutic window
• Maximum effect of antibiotic
• Risk of toxicity
• Examples: vancomycin and
gentamicin • Blood tests at specified time
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7
Q

Time dependent Vs. concentration dependent killing of bacteria

A

• Minimum inhibitory concentration used needed to kill bacteria • In time dependent – long half
lives beneficial, they spend
longer at the binding sites • In concentration dependent –
levels important, need a
certain concentration at the
binding sites

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8
Q

Why do we use antibiotics?

A
  • Short term management of bacterial infections • Prophylaxis in acute setting
  • High risk procedures • Long term prophylaxis
  • If suitable
  • Local UHL guidelines
  • Associated risks
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9
Q

why clavulanic acid and amoxicillin are co

prescribed as co-amoxiclav

A

• Synergistic effect • Examples: Tazocin, Co-trimoxazole
Co-amoxiclav
Clavulanic acid
Inhibits effect of some β lactamase enzymes so amoxicillin can work better
Amoxicillin
Acts on cell walls of bacteria in usual standard mechanism of action

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10
Q

What determines which antibiotic to give?

A
  • Multiple factors
  • What is the likely source of infection?
  • Sources lend themselves to common groups of bacteria
  • Is the patient in a ‘high risk group’?
  • Trends, previous results – including resistance patterns • Special groups
  • Hepatic / renal impairment / pregnancy • Allergies and reactions
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11
Q

Anti-microbial stewardship

A

• Does the patient need antibiotics?
• Effects of overuse – resistance and side effects • Starting broad (empirical treatment) and then narrowing to more
appropriate antibiotics
• Choice rationalised by appropriate samples, blood cultures, swabs etc
• UHL policy – ‘restricted’ antibiotics, need authorisation from
microbiology department
Identify • Isolate • Investigate • Inform • Initiate treatment
• Initiate treatment
A to F A – abroad B – blood born virus C – colonised D – diarrhoea (& vomiting) E – expectorating (cough) F – funny looking rash

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12
Q

When can acyclovir be used in the treatment of

herpes simplex virus?

A

Aciclovir is anti viral, multiple uses, prevents replication but doesn’t eradicate. Can also be used against varicella zosta virus. Used against herpes simplex type 1.

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13
Q

Haemostasis

A

Haemostasis – the recapitulation of the recapitulation
• Essential for life
Limits bleeding following injury – adhesion and activation of platelets
and fibrin formation
haemostatic plug + fibrin mesh → stable bleeding control • Thrombosis: pathological haemostasis – in the absence of bleeding
things gone wrong • Thromboembolic diseases are common
- deep vein thrombosis (DVT) and pulmonary embolism (PE)
- transient ischaemic attacks (TIA), ischaemic stroke
- myocardial infarction (MI)
- consequence of atrial fibrillation (AF) • Venous and intracardiac thrombosis driven largely by coagulation
cascade c.f. arterial thrombus mainly platelet rich

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14
Q

The coagulation cascade

A

• Anticoagulant drugs – prevent thrombus formation and thrombus
growing
Intrinsic pathway - all components within blood
Extrinsic pathway - tissue factor and other factors in endothelium
• Regulation of the coagulation cascade essential to prevent solidification
of all blood • Coagulation factors are present in blood as inactive zymogens
serine proteases and cofactors • Number of intrinsic inhibitors of this pathway including antithrombin III • Vascular endothelium and its regulation of many mediators also critical
for balance in coagulation cascade (and platelet activation) • Calcium is an important cofactor in many of the coagulation cascade
steps (think of chelators used in blood sampling)
.
Insert image

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15
Q

Heparin

A

• First heparin like compound isolated in 1916ish • Heparins produced naturally in mast cells and vascular endothelium • Extracted for pharmaceutical use from porcine intestinal mucosa,
bovine lung • Unfractionated heparins (UFH) are large 5-30 kDa • Low molecular weight heparins (LMWH) 1-5 kDa
produced in 1980’s • Inhibits coagulation in vitro and in vivo
- Enhance antithrombin III activity - ~ 1000-fold

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16
Q

Unfractionated heparin (UFH)

A

• ~ 45 polysaccharide unit mixture, fast onset of action t1/2 30min low
dose, 2h at higher doses – mixed elimination - unpredictable • Typically i .v. bolus and infusion, s.c. for prophylaxis with much lower
bioavailability • Binding to antithrombin (ATIII) causing conformational change and
increased activity of ATIII • To catalyse inhibition of thrombin (IIa), heparin needs to
simultaneously bind ATIII AND IIa. • Xa inhibition only needs ATIII binding
Insert image

17
Q

Low molecular weight heparins (LMWH)

A

Low molecular weight heparins (LMWH)
dalteparin enoxaparin
• Typically ~ 15 polysaccharides which are absorbed
more uniformly (units/kg dosing) • Almost always s.c. (enoxaparin i .v. in ACS) • Bioavailability > 90%, longer t1/2 ~ 2+h, independent of dose • More predictable dose response as does not bind to endothelial cells,
plasma proteins and macrophages – not long enough • Do not inactivate thrombin (IIa) – not long enough • Inhibition of Xa specifically – by enhancing ATIII activity
Dalteparin
Enoxaparin

• Fondaparinux – synthetic pentasaccharide selectively
inhibits Xa by binding to ATIII – s.c., t
1/2
18h
fondaparinux

18
Q

Compare unfractioned heparin and low molecular weight heparin

A

• Large negatively charged molecules – poor GI absorption • Given parenterally – i .v. or s.c.

Insert table

19
Q

Indications for use of heparins

A

• Prevention of venous thromboembolism
perioperative prophylaxis with LMWH duration and dose dependant on
risk • During pregnancy used as do not cross placenta – monitored with
caution • VTE – DVT and PE
initial treatment prior to oral agents (see later slides)
Long term in some patient groups
Cancer related VTE • Acute Coronary Syndromes
short term - reducing recurrence and or extension of coronary artery
thrombosis post STEMI - PCI and non PCI patients
NSTEMI

20
Q

Adverse reactions related to heparins

A

• Bruising and bleeding
Intracranial, at site of injection, GI, epistaxis
hepatic and renal impairment, elderly or those with carcinoma at
higher risk • Heparin induce thrombocytopenia (HIT) (~1/100 – UFH vs. ~ 1/1000
LMWH)
autoimmune response 2-14 days after initiation of heparin
antibodies to heparin platelet factor 4 complex
depletion of platelets
paradoxically can lead to thrombosis as more platelets activated by
damaged endothelium • Hyperkalaemia – inhibition of aldosterone secretion • Osteoporosis - rare long-term use, higher risk with UFH and more
prevalent in pregnancy

21
Q

Heparin monitoring and reversal

A

• (activated) partial thomboplastin time (aPTT) when using therapeutic
doses of UFH required – dose titrated against this value • LMWH much more predictable in its action so normally requires little
monitoring protamine sulphate
• Protamine sulphate forms inactive complex with heparin – given i .v.
dissociates heparin from ATIII, irreversible binding
amount given guided by heparin dose
can cause bleeding! in vitro test if unsure • Greater effect with UFH than
Protamine -
+ sulphate
LMWH, no affect on
+-
fondaparinux

22
Q

Vitamin K antagonists

warfarin

A

• Inhibit activation of vitamin K dependant clotting
factors (koagulation vitamin)
warfarin
Inhibits conversion of vitamin K to active reduced
form – competitive inhibition of VKOR • Hepatic synthesis of active clotting factors II, VII, IX and
X require active vitamin K as cofactor • Delay in onset of action as circulating active clotting
factors present for several days
- Must be cleared and replaced with noncarboxylated
forms (inactive clotting factors) • t1/2 ~36 - 48h (some variation)

23
Q

Indications for use of warfarin

A

• Venous thromboembolism
PE
DVT and secondary prevention
Superficial vein thrombosis • Atrial fibrillation with high risk of stroke (use CHA2DS2Vasc)
Cardioversion • Heart valve replacement bio prosthetic and some mechanical
PE- pulmonary embolism, DVT –deep vein thrombosis
• Generally used in longer term anticoagulation c.f. heparins • Slow onset of action likely to require heparin cover (see later slides) if
anticoagulation needed immediately

24
Q

Warfarin - pharmacokinetics

A

• Good GI absorption and taken orally ~95+% bioavailability • Functional CYP2C9 polymorphisms contribute to significant inter
individual variability • [Plasma] does not correlate directly with clinical effect • Warfarin is a racemic mixture of two enantiomers – R and S which have
different potency and metabolised differently • Crosses placenta – avoided at least in 1st (teratogenic) and 3rd (haemorrhage)
trimesters • Response affected by CYP2C9 and others, vitamin K intake

25
Q

Warfarin adverse drug reactions

A

• Principle ADR is bleeding – a patient taking warfarin is always of
clinical interest • Epistaxis and spontaneous retroperitoneal bleeding • Most effective antidote is vitamin K1
prothrombin complex concentrate i .v.
stop warfarin! • Perioperative anticoagulation needs to be considered
specific patient group and local guidelines will dictate
Bridging therapy with LMWH often required when initiating or temporarily stopping warfarin (surgery, sickness…)

26
Q

Warfarin drug-drug interactions

A

• Huge number of DDIs
majority potentiate anticoagulant action but some decrease effects • Inhibition of hepatic metabolism especially CYP2C9
Amiodarone, clopidogrel, intoxicating dose of alcohol, quinolone,
metronidazole…. • Reduce vitamin K by eliminating gut bacteria involved in production
-cephalosporin antibiotics • Displacement of warfarin from plasma albumin
NSAIDs and drugs that decrease GI absorption of vitamin K
-Likely increase INR • Acceleration of warfarin metabolism
barbiturates, phenytoin, rifampicin, St Johns Wort
-Likely decrease INR

27
Q

Warfarin use and INR

A

• Monitoring required due to huge variation in patient response • Keeping diet and lifestyle/medications stable is important • Factor VII most sensitive to vitamin K deficiency so used in prothrombin
time - standardised against control plasma
Referred to as international normalised ratio – INR - clotting time
against standard
Allows for standard corrected value comparable across all laboratories
As a guide and not an exhaustive list INR 2.5 • DVT
PE
AF (risk

28
Q

DOACs – the tide is turning?

A

• Direct acting oral anticoagulants (DOAC)
May see described as NOAC edoxaban rivaroxaban
• Direct Xa
Inhibit both free Xa and that bound with ATIII, do not directly effect thrombin (IIa) - hepatic metabolism and excreted partly by kidneys, t 1/2
~10h
• Direct IIa
dabigatran
Selective direct competitive thrombin inhibitor, both circulating and thrombus bound IIa, t
1/2
~9h
• Oral administration, standard dosing and little to no direct monitoring
required • Different DOACs are indicated in many presentations where vitamin K
antagonists used to be the only option

29
Q

DOACs the good and the bad

A

• Bleeding
Caution and dose adjustments particularly in GI bleed risk groups • Metabolism and elimination by several routes
dabigatran contraindicated in low creatinine clearance
others are at very low creatinine clearance (<15 mL/min) • Less frequent interactions than warfarin but affected by CYP inhibitors
and inducers
[plasma] reduced by carbamazepine, phenytoin and barbiturates
[plasma] increased by macrolides • Lower intracranial bleed risk c.f. warfarin • Little information on use in pregnancy and breastfeeding – avoid • Antidotes now available – andexanet and idarucizumab – watch this space

30
Q

Warfarin vs. apixaban in AF patients

A

Panopto