Common Drugs - Dosing and Monitoring

1
Common Drugs - Dosing and Monitoring
PHENYTOIN

• Toxic? Me? With My Therapeutic Window?

2
Introduction

• This module is designed to help with your
  learning around some common drugs which you will
  be prescribing during your FY1 and FY2. As with
  many of the drugs we prescribe they are
  potentially very dangerous, are commonly
  mis-prescribed and there remains a mythology
  around them which lead to many of the errors
  associated with their use.
• Indeed the mere mention of these drugs on a ward
  round or in a clinic is often enough to bring
  even the most confident medic to their knees! By
  completing this module you should achieve a level
  of competence and safety which will mean you need
  rarely worry about them ever again. But if you
  are worried you can always log on and re-do the
  module!

3
Aims and Objectives

• By completing this module you should be able to
• appropriately prescribe gentamicin, digoxin,
  warfarin, heparin, Insulin, steroids and
  phenytoin
• monitor drug therapy by taking appropriately
  timed drug levels for gentamicin, phenytoin,
  digoxin and warfarin
• write up an IV insulin sliding scale and insulin
  infusion
• convert a patient from IV insulin to regular
  subcutaneous dosing
• appropriately prescribe anticoagulation
  intravenously, subcutaneously and orally.
• recognise the common side effects and toxicity of
  gentamicin, warfarin, digoxin, phenytoin and
  steroids.
• institute appropriate management to deal with
  toxic and other side effects

4
Drug (1) Gentamicin (no y) and the
aminoglycosides
5
Challenging practice

• A 78 yo woman presents in AE with severe urinary
  sepsis. She has hypertension but is otherwise fit
  and well. She is on Bendrofluazide 2.5mg od.
• Her UEs are Na131mmol/l, K 3.5mmol/l Urea 13.8
  mmol/l, Creatinine 127µmol/l.
• (1) Prescribe a stat dose of gentamicin.
• (2) When would you check the levels around the
  next dose?
• (3) How long will you continue the gentamicin?

6
Gentamicin

• Indications
• Principally used against clinically significant
  gram negative sepsis E. Coli, Proteus,
  Klebsiella, Pseudomonas (Tobramycin may be
  preferred for pseudomonas infection)
• Some anti-Staphylococcal effect (but is commonly
  used in combination with other anti
  staphylococcal agents)
• Also used in eye and ear infections (see
  introductory slide!)
• Why do we need to monitor?
• Like many of the drugs in this module, gentamicin
  has a narrow therapeutic window (NTW) which means
  toxicity, particularly ototoxocity and
  nephrotoxicity, can be a serious complication of
  treatment.

7
Gentamicin Dosing - I

• Previously (on ER) Gentamicin was given
• (a) In relatively small, standard doses to all
  patients regardless of weight, age and renal
  function i.e. 80 mg TDS regime
• (b) Often over inappropriately long periods
  e.g. 7 days
• This led to toxicity Particularly when levels
  were unavailable / not done!

8
Gentamicin Dosing - II

• Now superseded by dosing with initial
• Big Bolus dose (see next slide)
• (Max 400mg total)
• Measure trough LEVELS after approx 12 hrs
• Then depending on indications and patient
• Further ONCE a day dosing
• Generally not given for longer than 3 5 days
  unless exceptional circumstances e.g.
  endocarditis
• In endocarditis and pregnancy - The same dose
  (i.e. the once a day dosing) is split into BD or
  TDS regime
• NB A wise person once pointed out to me that
  one should be very wary of giving ototoxic drugs
  to blind people It is not an absolute
  contraindication but think about this!

9
Gentamicin Dosing Rule of Thumb

• Normal creatinine clearance - Gentamicin Dose
• 3 5 mg / kg
• Reduced creatinine clearance Gentamicin Dose
• 1 2 mg /kg
• The following formula can be used to calculate
  creatinine clearance in order to determine the
  doses and dosing interval when prescribing
  gentamicin.
• Creatinine clearance (ml/min) (N - age
  (years) ) x Wt (kg)
•  
  serum creatinine (µmol/l)
• Where N 150 for female patients 160 for male
  patients gt70 years,170 for male patients lt70
  years
• This does rely on you knowing or guestimating
  patients weight correctly always err on the
  side of caution!
• Normal creatinine clearance is (male range 97
  137ml/min) and (female range 88 128 ml/min)
  i.e. approximately 100ml/min
• It decreases with age (by approx 1ml/min/year
  from aged 20yo), reduced lean body mass i.e.
  reduced muscle mass, gender (as above) and of
  course renal disease
• It is a useful guestimate of the Glomerular
  filtration rate (GFR).

10
Gentamicin Dosing - Infusion

• Gentamicin comes in 80mg vials. It is important
  to try and make your doses multiples of 40 to
  ease the nurses job in making up the infusion.
• Infusion
• 100ml 5 glucose or sodium chloride 0.9 over 60
  minutes (round to the nearest 40mg) to a maximum
  of 400mg.
• Doses 240 mg slow IV over 3 -5 minutes
• 240mg over 30 minutes (as above)
• Note it can be given IM with good effect BUT be
  wary of DIC and raised INR in the sick or
  anticoagulated patient.

11
Monitoring of Levels

• After the initial BIG BOLUS
• Take the trough level 6 14 hours POST dose
  (conventionally 12 hours)
• This trough level should be in the
  sub-therapeutic range. As shown on the graph lt1
  mg / l at 12hrs
• This applies to all subsequent pre-dose levels.
• If the trough or predose level is still in the
  therapeutic window (between the black lines), the
  next dose should be missed or delayed.

12
Monitoring of Levels - II

• Pre level (Trough) lt 1mg/l
• Post level (Peak) gt 8 mg/l
• The post dose level is taken a minimum 30 minutes
  after dose usually measured 1 hour post dose.
• You dont want it to be toooo high as this will
  mean that much of the dose is above the
  therapeutic range and therefore will cause
  toxicity.
• Frequency of levels
• Ill patient monitor daily or once / three days
  Trough (Pre) level is important as are massive
  peaks.
• Stable patient STOP Treatment? Further levels
  once every three days
• Multiple dosing (BD and TDS) take levels after
  second (bd) or third (tds) dose then rules above
  apply.

13
Gentamicin challenge

• You are the FY1 doctor on acute medical on-call.
  The next patient Mrs DB (DOB 18.12.46) is a
  previously fit and well woman who presents to AE
  with a 24 hour history of delirium and offensive
  urine. She is haemodynamically stable.
• Your SpR has asked you to give her a stat dose of
  gentamicin and then write up her up for a course
  of IV cefuroxime.
• UEs Na 142 K4.9 Urea 11.6 Cr 120
• Her weight is guestimated at 80Kg
• Calculate her creatinine clearance
• How does this affect your dosing of her
  gentamicin?
• Using the drug chart provided write up the
  gentamicin and course of IV cefuroxime.
• What other therapeutic interventions will you
  write up?

14
Gentamicin challenge - Answers

• (1) Creatinine clearance (ml/min) (N - age
  (years) ) x Wt (kg)
  serum creatinine (µmol/l)
• (150 60) x 80 60ml/min
• 120
• Please note her age will increase by 1 year for
  each year this module is up and running! Change
  the calculation and answer accordingly.
• (2) This is a significantly reduced creatinine
  clearance and thus this patient should receive a
  maximum of 1-2 mg /kg i.e. maximum dose 160mg
• (3) See the chart on the next slide
• (4) She should also be written up for IV fluids,
  anti-emetics and any regular medications.

15
So thats what a slightly out of focus drug chart
looks like!
16
Anticoagulation
The verbs to Heparinise and to Warfarinise
17
Challenging Practice

• Remember neither Heparin nor Warfarin thin the
  blood. They both stop the blood clotting!
• List three indications for heparin
• List three side effects of heparin
• Why may you use IV unfractionated heparin rather
  than SC low molecular weight heparin?
• Which drug is used to reverse the anticoagulant
  effects of heparin?

18
Heparin

• Naturally occurring glycosaminoglycan
• Discovered in 1916 at John Hopkins University but
  was not used clinically in humans until the
  1930s.
• Derived from liver cells (Hepar is the Greek
  for Liver)
• Two forms Unfractionated heparin (UH) and
  fractionated, low molecular weight heparin (LMWH)
• May be given subcutaneously or intravenously
• Should NEVER be given IM (think about it!)

19
Unfractionated Heparin (UH)

• Given intravenously
• Advantages
• - Rapidly reversed by turning off the infusion
  (typically half life is 30minutes, so APTT will
  return to normal within this period)
• - This it is still used in patients where they
  may be at risk of bleeding but still need
  anticoagulation other indications include
  surgical patients, renal failure patients and
  cardiac catheter patients
• Disadvantages
• - Binds unpredictably and non-specifically to
  plasma proteins, macrophages and vascular
  endothelium leading to an unpredictable response
  to dosing.
• - Binding to plasma proteins can lead to heparin
  resistance, where very large doses are required
  to achieve anticoagulation.
• Side effects
• - Bleeding if clinically significant needs to
  be reversed by (a) stopping the heparin and (b)
  giving IV protamine infusion or FFP
• - Heparin Induced Thrombocytopaenia HIT
  heparin binds to platelet factor 4 forming a
  complex. UH may induce the production of an
  auto-antibody against this complex, which in turn
  causes thrombocytopaenia. Paradoxically (despite
  low platelets) there is an extension of existing
  thrombus and risk of further thrombosis.
• - Osteopaenia UH binds to osteoblasts,
  activating osteoclasts and thus leasds to
  osteopaenia. This is only of concern in patients
  who need long term heparin e.g. pregnant women
  who have had a DVT or PE early in their pregnancy
  (Warfarin is contraindicated)

20
Unfractionated Heparin (UH)

• Dose (IV)
• Load with 4000 - 5000units stat (IV)
• Typically patients are then given between 20,000
  and 50,000 units over 24hours (depending
  principally on their lean and total body weight)
• Therapeutic level aim to keep APTT at
• (2 3 x control - approx 60 90 seconds)
• Monitor therapy by performing APTT at steady
  state (6 hours after the infusion begins)
• Dose and infusion should then be adjusted
  accordingly (see http//www.hscj.ufl.edu/resman/ma
  nualpdfs/Heparin_Orders_Med_Surg_Crit_Care.pdf )
• APTT needs to be checked at least once every
  24hours after therapeutic level is achieved.

21
A quick calculation http//www.hscj.ufl.edu/res
man/manualpdfs/Heparin_Orders_Med_Surg_Crit_Care.p
df

• Mr James Watt is a 43yo man (d.o.b 12/04/63)
  (hospital number 203864) who is to be admitted
  from AE with a suspected pulmonary embolism. He
  is guestimated to be 80Kg. He has no known drug
  allergies.
• Using the link (above) and the IV heparin
  protocol provided
• Write up the recommended heparin infusion on a
  fluid chart.
• Please work out the rate of the infusion in
  units/hour and ml/hour.
• At 6hours his APTT is 124seconds. Please
  recalculate the infusion rate in units/hr and
  ml/hr.

22
Mr Watt The answers

• According to the protocol
• Write up an infusion of 25,000units of heparin in
  250ml 5 dextrose (D5W) i.e. 100units/ml Mr Watt
  is 80kg
• He should have had a stat dose of 5000u heparin
  IV (which would have been written on the drug
  chart once only section)
• The infusion rate for a patient with a PE should
  run at 15units/kg/hr (15x80)u/hr 1200u/hr
• If 100u/ml, this means the initial infusion rate
  is 12ml/hr.
• If the APTT is 124 seconds the protocol
  recommends that the infusion be turned off for 1
  hour and then re-started at a rate of 3u/kg/hr
  less than before i.e. 12u/kg/hr
• Thus new infusion rate (12 x 80)u/hr 960u/hr
  9.6ml/hr
• See next slide for fluid chart

23
Mr Watts - the answers
24
Fractionated LMWH

• Derived by fractionation or depolymerisation of
  the larger and longer chained, naturally
  occurring unfractionated heparin
• Thus they are smaller molecules with shorter
  polysaccharide side chains
• Principally work by blocking coagulation factor
  Xa (unlike UH which also blocks the action of
  thrombin)
• They have less affinity to plasma proteins,
  macrophages, endothelium and osteoblasts
• These features mean they
• - cause less of the side effects of UH e.g.
  H.I.T and osteoporosis
• are more predictable in effect.
• have a longer half life and therefore need only
  be given once or twice / 24 hours
• can be administered subcutaneously
• Disadvantage the long half life means they are
  less easily reversed so are not used in high
  risk patients or those with need for rapid,
  simple reversal of their anticoagulation e.g.
  prior to operative intervention.
• Side effects Bleeding Other side effects are
  similar to UH but at a far lower incidence .
• However they can NOT be used as a substitute for
  UH in patients with H.I.T In this case the
  heparinoid Danaparoid is used. Not to be
  confused with the antipsychotic Danisparanoid

25
LMWH Indications and Doses

• Indications ACS, DVT and PE treatment and
  prophylaxis i.e. similar to those of UH but LMWHs
  are now are used as the heparins of choice.
• Two LMWH are commonly used in the UK Enoxaparin
  (Clexane) and Dalteparin (Fragmin) Both are
  given subcutaneously
• Both are dosed by units or mg / kg (thus you need
  to know or guestimate the patients weight)
• Most hospitals will produce dose/Kg protocols for
  all their main indications

26
LMWH
Indication Enoxaparin (Clexane) Dalteparin (Fragmin)
Medical DVT prophylaxis 40mg od 5000iu od
Surgical DVT / PE prophylaxis 40mg 12hours prior to operation 40mg for each day post-operative that heparin is indicated 5000iu 12hours prior to operation 5000iu for each day post-operative that heparin is indicated.
Treatment of DVT or PE 1.5mg/kg od Or 1mg/kg bd 100iu/kg - bd
ACS 1mg/kg bd 120iu/kg bd
27
When to stop the Heparin

• If the patient is on prophylaxis for DVT/PE the
  heparin may be stopped once they are mobilising
  well and clinically improving.
• In patients with ACS the heparin is stopped
  when they are pain free and mobilising well.
• In orthopaedic patients who have undergone total
  hip replacement there is evidence to suggest that
  they should stay on heparin for several months
  post-operatively (although this is still not
  common practise).
• For medical patients you should think whether the
  patient would benefit from long term
  anticoagulation with warfarin e.g. patients with
  AF.
• In patients starting warfarin for DVT or PE,
  warfarin is started as soon as the diagnosis is
  confirmed. The heparin is then continued until
  the patients INR gt 2.0.
• However there is evidence that patients should
  stay on the heparin for several days from the
  time of their admission or diagnosis. This varies
  from 5 to 10 days (and is additional to the
  initiation of warfarin) this is not common
  practise in the UK.
• DVT therapy is now commonly initiated as an
  outpatient (from the AE department) BUT all
  patients should be followed up to consider
  possible underlying causes.

28
Heparin Links

• http//www.mja.com.au/public/issues/177_07_071002/
  eik10205_fm.html
• Nice summary of LMWH treatment
• http//www.rxkinetics.com/heparin.html
• Nice summary of UH treatment (a little
  technified at the end!)
• http//www.bcshguidelines.com/pdf/heparin_220506.p
  df
• British Society for Haematology guidelines for
  heparin therapy hot off the press 2006
• http//www.hscj.ufl.edu/resman/manualpdfs/Heparin_
  Orders_Med_Surg_Crit_Care.pdf

29
coumARIN anticoagulant

WARFARIN
30
Challenging Practice

• List three indications for Warfarin therapy
• Write up a loading regime for a 41yo woman who is
  on subcutaneous heparin and has just had a left
  lower limb DVT confirmed
• List the essential steps before discharging a
  patient on Warfarin
• A 71yo man who is on long term warfarin treatment
  presents in AE with a torrential epistaxis. He
  is haemodynamically stable but his INR is 9.9.
  What is your management?

31
Warfarin

• The most famous coumarin anticoagulant (name
  another!)
• Developed at The Wisconsin Alumni Research
  Foundation ( http//www.warf.ws/ - for the
  non-believers!)
• Hence its name WARFarin
• Indications
• - Venous thrombo embolic disease
• - Pulmonary embolism
• - Arterial thrombosis
• - Atrial fibrillation / Stroke prophylaxis
  (primary and secondary)
• - Prosthetic heart valve
• - Left ventricular aneurysm and large
  intra-cardiac thrombus (primarily seen post MI)
• Main side effect Increased risk of bleeding
• Famously causes idiosyncratic skin necrosis at
  large doses see (http//pathology.uc.edu/LABLI
  NES/V7I6.pdf )

Warfarin induced skin necrosis
32
Monitor INR

• Therapeutic levels based on INR
• Target
• INR 2 3 DVT, PE, AF, Arterial thrombosis
• INR 3 4 Metallic heart valve
• Warfarin levels will not reach steady state for
  several days so early INRs may be misleading

33
Drug Interactions With Warfarin
Drugs that Increase INR Increase effect includes Enzyme inhibitors Drugs that Decrease INR Reduce effect includes Enzyme inducers
NSAIDs Phenytoin
Omeprazole / Cimetidine Carbamazepine
Macrolides Rifampicin
Ciprofloxacin Oral Contraceptives
Flu/Ketoconazole Griseofulvin
Isoniazid
Trimethoprim
Amiodarone / verapamil
aRetrovirals

34
Fennerty nomogramFennerty A, Thomas P,
Backhouse G, Bentley DP, Campbell IA, Routledge
PA.  Flexible induction dose regimen for warfarin
and prediction of maintenance dose.  Br Med J
1984 2881268-70.

• This protocol was designed to
• achieve a target  INR of 2 to 3 relatively
  quickly.
• reduce the risk of overanticoagulation which is
  more likely to occur in patients who exhibit
  greater sensitivity to warfarin (eg elderly
  patients, patients with liver disease, inadequate
  nutrition, or CHF).
• However it does not eliminate INR overswings
  entirely,
• and a lower loading dose of 5mg may be used in
  patients
• thought to be especially at risk.
• It now appears in a modified form in the specific
• anticoagulation part of many Trust drug charts
  (I.e. you
• dont have to memorise it!)

35
Warfarin Dosing - II

• Day INR Warfarin dose (mg)    Predicted
  maintenance dose 4th Day
• 1st lt 1.4 10    INR Warfarin (mg)
• 2nd lt 1.8 10 lt1.4 gt8
• 1.8 1.0   1.4 8
• gt 1.8 0.5     1.5 7.5
• 3rd lt2.0 10    1.6-1.7 7
• 2.0-2.1 5  1.8 6.5
• 2.2-2.3 4.5  1.9 6 
• 2.4-2.5 4  2.0-2.1 5.5
• 2.6-2.7 3.5  2.2-2.3 5
• 2.8-2.9 3 2.4-2.6 4.5 
• 3.0-3.1 2.5  2.7-3.0 4
• 3.2-3.3 2  3.1-3.5 3.5 
• 3.4 1.5  3.6-4.0 3
• 3.5 1.0 4.1-4.5 Miss out next day's
  3.6-4.0 0.5 
  dose, then give 2mg 
• gt4.0 0        gt4.5 Miss out 2 days' doses
  then give 1mg
•     

36
Warfarin and Haemorrhage

• Haemorrhage is the principal side effect of
  warfarin therapy
• The risk is said to increase exponentially once
  INR goes above 5.0 particularly spontaneous
  intra-cranial haemorrhage
• However 50 of patients who have bleeds whilst on
  warfarin have INRlt 4.0
• The risk of haemorrhage is increased by
• - Increasing age gt 65yo (although this is
  multifactorial and may be related more to
  increased co-morbidities and polypharmacy)
• - Co-morbidities liver disease, hypertension,
  renal failure, thrombocytopaenia and coagulopathy
• - Drugs enzyme inhibitors, alcohol excess,
  NSAIDs
• - Previous GI or other significant haemorrhage.

37
Bleeding Hell! What to do about it

• Major bleedingstop warfarin give vitamin K1 -
  5 mg by slow intravenous injection give
  prothrombin complex concentrate PCC (factors II,
  VII, IX and X) 50 units/kg or (if no concentrate
  available) fresh frozen plasma 15 m/kg
• INR gt 8.0, no bleeding or minor bleedingstop
  warfarin, restart when INR lt 5.0 if there are
  other risk factors for bleeding give vitamin K1
  0.5 mg by slow intravenous injection or 5 mg by
  mouth (for partial reversal of anticoagulation
  give smaller oral doses of vitamin K e.g.
  0.52.5 mg using the intravenous preparation
  orally) repeat dose of vitamin K if INR still
  too high after 24 hours
• INR 6.08.0, no bleeding or minor bleedingstop
  warfarin, restart when INR lt 5.0
• INR lt 6.0 but more than 0.5 units above target
  valuereduce dose or stop warfarin, restart when
  INR lt 5.0
• Unexpected bleeding at therapeutic levelsalways
  investigate possibility of underlying cause e.g.
  unsuspected renal or gastro-intestinal tract
  pathology
• British Society for Haematology Guidelines as
  per BNF 2003

38
For the Warfarin addicted .

• http//www.acforum.org/doc_education_management.pp
  t316
• Another very nice overview of warfarin therapy
  with really pretty slides! A little out of date
  in parts but very good on the basic science.
• http//www.bcshguidelines.com/pdf/oralanticoagulat
  ion.pdf
• British Society for Haematology guidelines (2005)
  on oral anticoagulation everything you want to
  know and more!
• http//www.mja.com.au/public/issues/181_09_011104/
  bak10441_fm.htmlCHDDCIFC
• Another excellent overview from our friends down
  under good on ya!

39
Be warned!

• All patients placed on warfarin should be booked
  into a specialist anticoagulation clinic before
  being discharged.
• They should receive an anticoagulation booklet
  once established on warfarin
• Because it is a commonly prescribed drug which
  has potentially serious side effects, multiple
  interactions and complex follow up, warfarin is
  the beloved drug of exams and examiners in the
  latter phase of the course
• Lots of OSCE potential there!

40
Digoxin
41
Challenging Practice

• List two indications for digoxin
• List three biochemical abnormalities which will
  potentiate digoxin toxicity.
• List the common ECG changes seen with digoxin.
• What is the name of the drug used in severe
  digoxin toxicity?

42
Digoxin

• Digoxin is a cardiac glycoside derived from the
  Foxglove plant Digitalis purpurea
• Has been used by native tribesmen for centuries
  as a toxin for their darts and arrows
• First used for cardiac conditions by the Romans
• Famously described by William Withering in 1785
  as a treatment for Dropsy (oedema)
• Indications
• Supraventricular tachyarrythmia (AF,
  Aflutter) More recently its use is being
  superseded by betablockers, rate limiting calcium
  channel blockers, as well as amiodarone.
• - Heart failure likewise, its use has become
  restricted to end stage disease
• Caution Reduced Creatinine clearance (see
  gentamicin section) Hypokalaemia
• Toxic effects potentiated by Hypokalaemia,
  hypomagnesaemia (both commonly caused by diuretic
  therapy) and hypercalcaemia. Both hypomagnesaemia
  and hypercalcaemia interfere with its effect on
  Na/K ATPase.

43
Digoxin Dosing

• Loading (PO or IV)
• - Patient needs ECG monitoring
• - Loading dose 250 500 mcg (depending on
  creatinine clearance)
• - Further similar, repeat dose is given 8 hours
  later
• - Maintenance dose at 24 hours (from first
  loading dose) 62.5 125 mcg
• - If rate is still poorly controlled dose can be
  increased in 62.5mcg increments to a maximum of
  250 mcg / day

44
Side effects and interactions

• Side effects
• Arrhythmia (classically bradycardia and various
  degrees of heart block. Allegedly digoxin
  toxicity may cause any tachy or bradyarrhythmia!)
• Nausea and vomiting, diarrhoea.
• Slow (bradycardia) and Sick Digoxin toxicity
  
• Fast (tachycardia) and Sick
  Aminophylline toxicity
• Dizziness and confusion.
• Famously Xanthopsia Yellow (and green)
  colouring of the vision
• In practice most patients (including the
  elderly!) have no problems on digoxin (Despite
  its NTW and their co-morbidities)
• Interactions
• Bradycardia inducing agents betablockers, rate
  limiting calcium channel blockers, amiodarone
• Quinidine
• Erythromycin

45
Monitoring therapy

• Levels are taken on day (7 or after) of therapy
  as this is when steady state is reached. Levels
  taken before this can often be misleading.
• The level is taken at least 6 hours after the
  last dose (this may also be a cause of false
  concern when levels performed on admission fall
  well within this 6 hour cut-off.)
• However very low or non-existent concentrations
  on admission may confirm the diagnosis of poor
  compliance.
• Normal range 1.0 2.6 nmol/l
• This may vary according to different labs
• Toxicity may occur within the normal range when
  other factors e.g. hypokalaemia exist.

46
Digoxin Toxicity

• Toxicity often presents with non-specific signs
  and symptoms and as with any patient on
  medications one needs a very high index of
  suspicion!
• Remember
• - Drugs cause everything!
• - Slow and Sick Digoxin toxicity
• - The reverse tick sign on an ECG is a sign of
  digoxin therapy
• and not toxicity!
• - Regular VEBs, Bradycardia, heart block and
  arrhythmia may
• all be signs of digoxin toxicity
• Correct hypokalaemia and other biochemical
  abnormalities
• Correct treatable causes of renal impairment
• For Severe Toxicity / Overdose one can give
  (Digibind ) an IV preparation made of
  Digoxin-specific antibody fragments.

47
DIGOXIN Challenge

• A 78yo man with COPD presents in AE with a right
  lower lobe pneumonia and fast AF.
• UEs Na 141mmol/l, K 4.1 mmol/l Urea 32.8
  mmol/l, Creatinine 140µmol/l.
• He is guestimated to weigh 60kg. He has no known
  allergies.
• The lovely 3rd year medical student has written
  up the patients details for you.
• Calculate his creatinine clearance
• Write up the loading and maintenance doses of
  digoxin on your charts. You should also write up
  the other medications you would give him.
• List three other investigations he may require.

48
Digoxin challenge - Answers

• (1) Creatinine clearance (ml/min) (N -
  age (years) ) x Wt (kg)
•  
  serum creatinine (µmol/l)
• (160 78) x 60 35.1ml/min
• 140
• (2) See charts on the next 3 slides for answers
• (3) FBC, Repeat UEs, Calcium and magnesium,
  Blood and sputum cultures
• Chest radiograph
• ECG
• ABGs
• When heart rate is improved - Echocardiogram

49
So just how many did you get?
50
and theres more!
51
References

• http//www.emedicine.com/med/topic568.htm
• Recommended review on e.medicine

52
Insulin and Sliding Scales
53
Challenging practice

• What are the main differences between the
  previous generation of insulins and human
  analogue insulins?
• Write up an insulin sliding scale, insulin
  infusion and IV fluids for a type 2 diabetic who
  has been admitted for a left total knee
  replacement tomorrow morning.

54
Common insulin Regimes used in Diabetes

• Single Dose Intermediate or long acting insulin
  (/- Metformin)
• BD Regimen Mixed Short / rapid and Intermediate
  acting insulin
• QDS (Basal bolus) Regimen TDS Short / rapid
  acting Nocte Intermediate / long acting insulin
• Sliding Scale HONK DKA Peri-operatively
  Severely ill or patients who are NBM.

55
Human analogue insulins

• The previous generation of insulins are slowly
  being phased out by the newer insulin analogues.
• In the 1980s most insulin was derived from bovine
  or porcine sources.
• Then human insulin was genetically produced.
• Today a new generation of insulin analogues are
  being produced by human recombinant DNA
  technology.

56
Whats the advantage of the rapid acting
analogues?

• The short or rapid acting analogues are said to
  be more physiological in their action I.e. they
  can be used to more closely mimic the profile of
  endogenous insulin secretion.
• They are monomeric insulin molecules and this
  means they are more rapidly absorbed.
• This in turn means they have a more rapid onset
  of action and peak effect.
• For the patient this means they can be taken WITH
  or just after a meal. Rather than the 30minutes
  prior to a meal as was required with the previous
  generation of insulins
• This has enabled diabetic patients to live far
  more normal chaotic lives that the rest of us
  take for granted.

57
Whats the advantage of the rapid acting
analogues?

• They have a shorter half life than previous
  insulins which means their effects are eliminated
  more rapidly.
• This has led to reduced hypoglycaemic episodes
  particularly at night (nocturnal hypoglycaemia)
• However despite these positive differences these
  have so far not translated into major differences
  in glycaemic control.

58
The advantage of long acting analogues

• The long acting analogue Glargine has full 24
  hour coverage.
• This means it can theoretically be given at any
  time of the day or night which best suits the
  patient.This needs to be the same time each day.
• Conventionally this is usually at breakfast or
  bedtime.
• Caution however must be used in patients with
  significant renal impairment (DM is the commonest
  cause of ESRF in the UK) because of its long half
  life.
• With reduced excretion there may be a lag
  effect into the next day, increasing the risk of
  hypoglycaemia.

59
Human analogue insulins
Insulin Trade name Duration of action Superseding
Insulin Lispro Humalog Rapid acting Actrapid insulin
Insulin aspart Novorapid Rapid acting Actrapid insulin
Lispro and Lispro protamine suspension Humalog mix25 (25 short acting 75 intermediate) Mix of intermediate and short acting
Insulin aspart and aspart protmaine suspension Novomix 30 (30 short acting 70 intermediate) Mix of intermediate and short acting Mixtard 30/70 Actrapid and isophane
Glargine Lantus Long acting Monotard or ultratard
Insulin zinc suspension Humulin L (lente) Long acting
Insulin detemir Levemir Long acting
60
Sliding Scale Insulin

• Basic Indication Hyperglycaemia and acute,
  severe illness
• E.g. DKA, HONK coma, ACS, Stroke, Peri-operative
  patients, severe sepsis, prolonged diarrhoea and
  vomiting, the unconscious diabetic patient.
• If possible it is always better to leave the
  patient on their regular insulin regime
• Given IV IV access is very important but may be
  quite difficult in the very sick patient
  (Theoretically insulin can be given IM as hourly
  boluses but in practice this is never done With
  IM injections it is very difficult to gain
  glycaemic control and sick patients may have
  contra-indications such as DIC)
• Previously sliding scales often lead to extreme
  swings in glycaemic control.
• This in turn led to rapid and harmful swings in
  potassium (hypokalaemia) and osmotic equilibrium
  (cerebral oedema)
• Now we use sliding scales which (hopefully) lead
  to a more gentle reduction in hyperglycaemia and
  stops the harmful swings in potassium levels and
  osmotic changes.

61
Sliding scale insulin

• It seems that every diabetologist in every
  hospital likes their own sliding scale.
• But some things should be true for all of them
• The Insulin infusion and fluids SHOULD run
  through the same venflon. This means you dont
  get one without the other!
• Potassium should be added to all bags of fluid
  unless the serum K is gt5.0mmol/l
• Type 1 diabetics should NEVER be without insulin
  even with low blood sugars the infusion should
  not be turned off for prolonged periods of time.
• The underlying problems must be treated.
• If the blood sugar does not come down you need
  to give the patient more insulin!This means
  re-thinking and re-writing the sliding scale
• Dextrose should not be given to hyperglycaemic
  patients until their blood glucose is 15mmol/l.
• Dont stop the sliding scale until the patient is
  (a) eating and drinking properly (b) clinically
  improved.

62
Example of Insulin sliding scale and infusion
Date Type of fluid Volume Added Rate Signature of doctor
02.09.06 Normal saline 50ml 50 units of Novarapid insulin According to sliding scale
02.09.06 Sliding scale Blood glucose Units per Hour
0 4.0 Zero (Type2 DM) 0.5 (Type1)
4.1 6.0 1.0
6.1 7.0 2.0
7.1 8.0 3.0
8.1 10.0 4.0
10.1 12.0 5.0
12.1 15.0 6.0
gt15.1 8.0

Remember You would also need to write up regular
fluids with potassium
63
Conversion from sliding scale to regular insulin
regime

• Patient should be clinically improving and eating
  and drinking adequate amounts.
• Ideally if the patient is a known diabetic they
  should be converted back to their regular insulin
  or oral hypoglycaemic agents.
• If this is not possible e.g. new presentation
  of diabetes, unknown regimen, insulin still
  required (wound healing and post MI) then a
  Basal bolus (QDS) regimen or less commonly a BD
  regimen should be calculated (see next slides)
• Conversion from sliding scale should occur during
  the early part of the working day to ensure no
  major problems occur. The sliding scale should be
  stopped just prior to the meal and the regular
  insulin administered with the meal (if a rapid
  acting analogue) or 30 minutes prior to the meal
  if a human or other insulin is being
  administered.

64
Conversion from sliding scale to basal bolus
(QDS) insulin regimen

• For QDS regimen
• Divide the total dose of insulin in previous 24
  hours by two.
• Long acting (evening dose) approximately 80
  of one half.
• The 3 mealtime rapid acting doses
  approximately 80 of the other half divided into
  3 doses. Normally these would be equal doses in
  the morning and evening and a smaller dose at
  lunchtime.
• But this may vary according to patients meals.
• Although this sounds very didactic in fact it is
  an educated guestimate of the patients insulin
  requirements. You may find patients require very
  different doses once they are better.
• These are only suggested regimens and you may
  find others have very different and even more
  helpful views!
• E.g. A 23yo newly diagnosed diabetic patient is
  being converted from his sliding scale to regular
  QDS insulin. His total units of insulin over the
  past 24 hours has been 60 units.
• Total 60 units
• 60/2 30 units
• Thus evening dose of Glargine (80 of 30)
  24units
• Doses of Novorapid AM 8units Lunch 6units PM
  8units

65
Conversion from sliding scale to basal bolus
(QDS) insulin regimen

• Divide total insulin dose received over 24 hours
  by 2.
• BD regimen typically total insulin 2/3rd total
  in am 1/3rd in pm
• However you would once again give approximately
  80 of the total insulin units that had been
  given over the past 24 hours.
• E.g. A 63yo known type 2 diabetic man is
  recovering after major cardiac surgery. He is
  eating and drinking well but the surgeon would
  like him to remain on regular insulin to promote
  wound healing. He suggests a BD regimen. The
  patient has received 60 units of insulin in the
  past 24 hours on his sliding scale.
• Total 60units
• 80 of 60u 48u
• Using Novomix 30
• Morning dose 2/3rds (48u) 32u Evening dose
  1/3rd (48u) 16u.

66
Insulin sliding scale - Example

• Mrs Johnson, a 73yo type II diabetic, has been on
  an insulin sliding scale for the past 72 hours
  after being admitted with HONK pre-coma She is
  now eating and drinking normally and is currently
  on 3 units / hour of insulin. Her last blood
  glucose performed an hour ago 11.9 mmol/L.
• Convert her to a QDS or BD regimen using
  novorapid and glargine or novomix30. Please
  prescribe your calculated doses on the drug chart
  provided.

67
Sliding scale - Answer

• QDS regimen Glargine (nocte) and Novorapid
  (tds)
• 3u / hour 72 units in 24 hours
• 80 of 72 58 units 58/2 29units
• Novorapid breakfast 10u lunch 8u evening 10u
• Glargine 28units nocte
• BD Regimen Using Novomix 30
• 3u / hour 72 units in 24 hours
• 80 of 72u 58units
• Morning dose 2/3 of 58u 38units
• Evening dose 1/3 of 58u 18units
• All patients will require education re
  Monitoring Diet, complications and hypoglycaemic
  episodes.
• They should be seen by the diabetes nurse
  specialist prior to their discharge and follow up
  with the specialist diabetes services confirmed.

68
Steroid Therapy
Professors Knight and Fowler realised that their
hobby was getting out of hand!
69
Challenging Practice

• List 5 different routes of administration for
  steroid therapy with an indication for each.
• List 3 side effects of long term steroid therapy.
• (3) List 3 contraindications to steroid therapy

70
Steroids - Indications

• Indications
• Replacement for hypopituitarism and adrenal
  insufficiency ( Hydrocortisone orally tds or bd)
• Anti-inflammatory
• - Acute Asthma, COPD, Vasculitis, Allergy,
  Cerebral oedema (dexamethasone), Skin disease
  eczema, Eye disease uveitis, iritis
• - Chronic Inflammatory Bowel Disease (IBD),
  Rheumatoid arthritis, SLE, Myositis.
• Others hypercalcaemia of malignancy, meningitis
  in children (lt15yo), Pemphigus, AIHA, ITP,
  Demyelination
• NB Anyone on steroid therapy long term (but not
  on replacement therapy) Dont forget a Bone
  Sparing Agent (BSA)!

71
Give them the roids The Fat man, The House
of God

• Remember Never stop the steroids
• If patient is acutely unwell or stressed (e.g.
  peri-operative) they need more, not less
  steroids!

• Routes of Administration every possible way!
• Topical (ointments, creams, drops (eyes))
• Oral, IV, IM, PR (enema), Inhaler (nasal and
  oral), Nebuliser

72
Steroid dosing

• Hydrocortisone replacement (Hypopituitarism and
  Hypoadrenalism)
• Oral 10mg on waking 5mg lunchtime 5mg early
  evening.
• Note Hydrocortisone 20mg / 24 hours is the
  replacement dose required in most patients. This
  is equivalent to a patient on long term
  prednisolone 7.5mg / 24hours.
• Thus if a patient is on a long term dose of
  prednisolone gt7.5mg/24 hours this will suppress
  their Hypothalamic-Pituitary-Adrenal HPA axis.
• Therefore any patient who presents unwell on
  replacement hydrocortisone or on long term
  prednisolone gt 7.5mg / 24 hours they need to be
  given EXTRA steroids either IM or IV
• Give Hydrocortisone 50 100mg 6 hourly or as an
  IV infusion 1 -2mg / hour

73
Steroid dosing

• Acute Asthma
• Prednisolone 40mg od (preferably) or
  hydrocortisone 100mg 6 hourly
• Oral steroids are preferable over IV or IM
  therapy in any patient well enough to take
  tablets. However in the severely unwell patient
  IV or IM therapy should be given.
• Acute arteritis, allergy, connective tissue
  disease
• Prednisolone 40 60mg od or Hydrocortisone 100mg
  6 hourly.
• Intracerebral oedema
• Dexamethasone Loading dose 10mg IV (if unwell)
  Maintenance 2 4mg orally or IV /IM.
• All Patients should be on the LOWEST possible
  maintenance dose to keep them asymptomatic

74
Unwell Patients and steroids

• If a patient is on long term steroids or has
  known Addisons disease becomes acutely unwell,
  is NBM or stressed (e.g. major surgery) they
  should be given extra parenteral (IM or IV)
  steroid treatment.
• This also applies when the patient has suspected
  Addisons disease.
• IM is slow release and will give a smoother
  profile whilst IV gives large, acute peaks and
  then rapidly troughs because of its short half
  life.
• However IM dosing is contraindicated in patients
  with DIC or high INR.
• If IV 1 - 2mg / hour run in infusion over 24
  hours i.e. 24 48mg over 24hours
• Seek an endocrinology opinion in any patient who
  you are worried about.

75
Stopping Steroid Therapy

• Never stop long term steroid therapy abruptly.
• If the patient is acutely unwell they need more
  NOT less!
• If they are clinically stable slowly reduce the
  dose attempting to withdraw the steroids
  completely.
• All patients should be maintained on the lowest
  possible dose to keep them asymptomatic.
• Consider the use of other immunosuppressant
  agents e.g. azothioprine or methotrexate which
  may reduce the need for higher doses of steroids

76
For each of the following scenarios write out
your steroid prescription.

• A 23yo with an acute exacerbation of their asthma
  requiring admission. They are able to swallow
  tablets.
• A 79yo with possible temporal arteritis ( ESR
  112).
• A 24yo with Crohns disease now presenting with
  an acute abdomen. He is on maintenance of
  prednisolone 10 mg od
• A 57yo on hydrocortisone replacement post
  pituitary surgery is admitted with a severe
  community pneumonia and drowsiness.
• An 83yo with a large left cerebral hemisphere
  tumour, with surrounding oedema and mass effect
  to the right

77
Recommended doses

• Asthma Stat prednisolone 40mg (po) followed by
  5/7 (only) course of prednisolone 40mg. You
  should have also included an inhaled steroid e.g.
  beclomethasone, fluticasone or budesonide 2 puffs
  bd
• http//www.brit-thoracic.org.uk/c2/uploads/BGMA.06
  _Manag_asthma.ppt
• (2) Prednisolone 40mg PO od for 4 to 6 weeks,
  then slow reducing dose. Success of treatment
  judged by reduced ESR and clinical improvement.
• http//turner-white.com/pdf/hp_feb03_giant.pdf
• (3) And (4) To give hydrocortisone (IV) 24mg
  48mg over 24 hours (you will need to write an
  infusion e.g. 24mg in 48mls of n.saline to run IV
  at 2ml/hr. Or IM hydrocortisone 50 - 100mg qds).
• (5) Patients with raised intracranial pressure
  and cerebral oedema require dexamethasone PO, IM
  or IV 4mg qds. If acutely unwell - Initially (IV)
  10mg then 4mg (IM) 6hourly. If able to take
  tablets 4mg po QDS.
• http//www.bnf.org/bnf/bnf/current/4271.htm?q22d
  examethasone22_hit

78
Phenytoin
79
Challenging Practice

• List three reasons why a patient on Phenytoin may
  present with a seizure.
• List some drugs which may interfere with the
  metabolism of Phenytoin.
• How long after a dose should you take the
  Phenytoin level?

80
Phenytoin

• Indications
• Tonic -Clonic seizures
• Status Epilepticus
• Post-neurosurgical intervention
• Trigeminal neuralgia
• More recently it has become a second / third
  line therapy in primary epilepsy because of its
  nasty side effect profile and the need to
  monitor its effects.
• Therapy needs to be monitored because of
• Narrow Therapeutic window (NTW)
• Zero order kinetics i.e. Non-linear relationship
  between dose and plasma concentration. Thus,
  small increases in the dose may lead to
  unpredictable (large) rises in plasma
  concentration and precipitate toxicity.

81
Phenytoin side effects

• Acute (and chronic)
• Cerebellar syndrome nystagmus, ataxia,
  dysarthria.
• Paradoxical seizures can be a sign of toxicity
  and poor/non-adherence to therapy
• Nausea and vomiting
• Sedation and confusion thus it should be given
  as single night time dose.
• Chronic
• Aplastic anaemia and pancytopaenia
• Megaloblastosis (and anaemia) Drug effect and
  folate deficiency
• Hirsutism, coarse facies and acne
• Gingival hyperplasia
• Peripheral sensory neuropathy
• Thus proving DRUGS CAUSE EVERYTHING!

82
Phenytoin Dosing and Monitoring

• Phenytoin is still used very effectively in
  status epilepticus (see references)
• It requires a loading dose with the patient in a
  high dependency area, on an ECG monitor.
• Loading dose
• IV Infusion 15mg/kg run at a rate NOT
  exceeding gt 50mg/minute.
• Maintenance doses thereafter
• IV infusion 100mg 6 to 8 hourly
• When given IV it is very phlebitic and should be
  followed by a saline flush whenever possible.

83
Phenytoin Dosing and Monitoring

• Steady state is reached after 7 to 10 days
• 90 of the drug is protein bound in the serum
  thus significant hypoalbuminaemia will effect the
  drug levels.
• Significant renal impairment (i.e. creatinine
  clearance lt 20ml/min) will also effect the drug
  levels
• Calculating phenytoin level correction
• In hypoalbuminemia
• Corrected level Measured phenytoin level
• (albumin x 0.2) 0.1
• In renal failure CrCL lt 20 ml/min
• Corrected level Measured phenytoin level
• (albumin x 0.1) 0.1

84
Levels

• Post loading dose
• 2 to 4 hours (checks for significantly high
  levels i.e. potential toxicity)
• Trough level Immediately prior to the regular
  daily dose.
• - Taken on or after 10th day after starting
  regular therapy
• - This gives information about the accumulating
  level of the drug
• - Also checks patient adherence to drug
• Peak level Phenytoin levels peak 3 to 9 hours
  post dose Should be in the therapeutic range (as
  below)
• - Peak level is taken at 4 6 hours post dose
  This is essential to check for potential toxicity
• (Note that reference ranges may vary between
  laboratories and local reference ranges should be
  consulted)

Therapeutic Phenytoin levels 10 - 20 mg/l
85
Toxicity and overdose

• Because of its zero order kinetics
  (unpredictability of plasma concentration with
  change of dose) - the dose should be increased
  gradually by small 50mg increments.
• Once increased the dose should not be changed for
  several weeks.
• Its effect should be judged by monitored levels
  and clinical response
• Likewise, Phenytoin therapy should not be rapidly
  withdrawn unless there is a life threatening
  complication (It may lead to status epilepticus)
• Toxicity see side effects Usually cerebellar
  signs, reduced level of consciousness, coma,
  hypotension and bradycardia.
• Toxicity is potentiated by enzyme inhibitors.
• Patients who present with severe toxicity may
  require intubation and ventilation,
  cardiovascular support with inotropes and with
  very toxic levels haemodialysis may be required
  to remove the drug from the circulation.

86
Interactions (see Warfarin section)

• Phenytoin is an enzyme inducer (interferes with
  metabolism OCP and Warfarin, reducing their
  levels.)
• Plasma concentration increased by Enyme
  inhibitors - Increased TOXICITY
• Plasma concentration reduced by Enzyme inducers
  Reduced Effect
• Some drugs e.g. ciprofloxacin have a
  unpredictable effect on phenytoin levels.

87
Phenytoin Exercise

• A 34yo man presents to AE in status epilepticus
  which has been poorly responsive to IV and rectal
  doses of diazepam. He is estimated to be 75kg.
• His WCC 15.9x109/l
• RBG 7.1mmol/l
• Na 123mmol/l
• Otherwise his bloods are normal.
• (1) Please calculate and write up a prescription
  for a phenytoin infusion including the minimum
  time for the infusion.
• (2) His CT head scan is shown opposite. Please
  write out your further management.

88
Answers

1. 15mg/kg (75Kg) 15x75 1125mg total
2. The infusion is made up of a solution of
   phenytoin 50mg/ml thus the infusion will be
   1125/50 22.5ml
3. Maximum rate 50mg/min. The solution is 50mg/ml
   i.e. the rate is 1ml/min.Thus the infusion should
   run for a minimum of 1125/50 22.5 minutes. If
   the infusion is 22.5ml it makes the calculation
   easier to make it up to 30ml with normal saline,
   not 30ml of 50mg/ml (1500mg infusion) and run it
   over 30minutes.

89
Answers

• The CT head scan shows a large right sided
  primary brain tumour with surrounding oedema.
  There is little midline shift but there is
  evidence of raised intracranial pressure.
• His GCS will invariably be 7 as he is in
  status therefore he will require intubation and
  ventiltion (he would have require this for the CT
  head scan), IV dexamethasone and referral to a
  neurosurgical ITU.

90
References

• www.tufts.edu/med/neurosurgery/
• Wonderful image on first phenytoin slide
• http//www-clinpharm.medschl.cam.ac.uk/pages/teach
  ing/images/
• Excellent clinical pharmacology resource
• http//www.bnf.org/BNF/bnf/current/3617.htm
• BNF guide to management of status epilepticus