Session 12 Flashcards
Describe bacterial structure
• DNA present in nuclei and
plasmids • Cell membrane and wall • Other specialised features
how anti-microbials work Mechanisms
- 5 main methods
- Inhibiting cell wall synthesis
- Inhibiting nucleic acid synthesis
- Stopping metabolite production
- Inhibiting cell membrane synthesis
- Inhibiting protein synthesis
What’s the difference between bactercidal and bacteriostatic?
• 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
Classes of antibiotic
Insert table
Antibiotic resistance
- Example
- Beta lactamase enzymes
- Efflux pumps • Plasmid DNA can be passed from cell to cell
• Why do we need to monitor?
• Narrow therapeutic window • Maximum effect of antibiotic • Risk of toxicity • Examples: vancomycin and gentamicin • Blood tests at specified time
Time dependent Vs. concentration dependent killing of bacteria
• 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
Why do we use antibiotics?
- Short term management of bacterial infections • Prophylaxis in acute setting
- High risk procedures • Long term prophylaxis
- If suitable
- Local UHL guidelines
- Associated risks
why clavulanic acid and amoxicillin are co
prescribed as co-amoxiclav
• 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
What determines which antibiotic to give?
- 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
Anti-microbial stewardship
• 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
When can acyclovir be used in the treatment of
herpes simplex virus?
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.
Haemostasis
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
The coagulation cascade
• 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)
.
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Heparin
• 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
Unfractionated heparin (UFH)
• ~ 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
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Low molecular weight heparins (LMWH)
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
Compare unfractioned heparin and low molecular weight heparin
• Large negatively charged molecules – poor GI absorption • Given parenterally – i .v. or s.c.
Insert table
Indications for use of heparins
• 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
Adverse reactions related to heparins
• 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
Heparin monitoring and reversal
• (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
Vitamin K antagonists
warfarin
• 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)
Indications for use of warfarin
• 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
Warfarin - pharmacokinetics
• 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
Warfarin adverse drug reactions
• 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…)
Warfarin drug-drug interactions
• 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
Warfarin use and INR
• 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
DOACs – the tide is turning?
• 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
DOACs the good and the bad
• 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
Warfarin vs. apixaban in AF patients
Panopto
