Transcript Common Drug Dosing and Monitoring Problems

Common Drugs - Dosing and
Monitoring
PHENYTOIN
Toxic? Me? With My Therapeutic Window?
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!
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
Drug (1) – Gentamicin
(no ‘y’)
and the aminoglycosides
Challenging practice
A 78 yo woman presents in A&E with severe urinary
sepsis. She has hypertension but is otherwise fit and
well. She is on Bendrofluazide 2.5mg od.
Her U+Es are Na+131mmol/l, K 3.5+mmol/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?
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.
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!
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!
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 >70 years,170 for male patients <70 years
This does rely on you knowing or guestimating patient’s 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).
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.
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 <1 mg / l at 12hrs
• This applies to all
subsequent pre-dose
levels.
• If the trough or pre–dose
level is still in the
therapeutic window
(between the black lines),
the next dose should be
missed or delayed.
Monitoring of Levels - II
Pre level – (Trough) < 1mg/l
Post level (Peak) > 8 mg/l
• The post dose level is taken a minimum 30 minutes after dose –
usually measured 1 hour post dose.
• You don’t 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.
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
A&E 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.
U&Es: Na+ 142; K+4.9; Urea 11.6; Cr 120
Her weight is guestimated at 80Kg
1.Calculate her creatinine clearance
2.How does this affect your dosing of her gentamicin?
3.Using the drug chart provided write up the gentamicin and course of
IV cefuroxime.
4. What other therapeutic interventions will you write up?
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, antiemetics and any regular medications.
So that’s what a slightly out of focus
drug chart looks like!
Anticoagulation
The verbs to Heparinise and to Warfarinise
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?
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!)
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)
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/manualpdfs/Heparin_Orders_Med_Surg_Crit_Care.pdf )
• APTT needs to be checked at least once every
24hours after therapeutic level is achieved.
A quick calculation …
http://www.hscj.ufl.edu/resman/manualpdfs/Heparin_Orders_Med_Surg
_Crit_Care.pdf
Mr James Watt is a 43yo man (d.o.b 12/04/63)
(hospital number 203864) who is to be admitted
from A&E 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
(1)Write up the recommended heparin infusion on a
fluid chart.
(2)Please work out the rate of the infusion in
units/hour and ml/hour.
(3)At 6hours his APTT is 124seconds. Please
recalculate the infusion rate in units/hr and ml/hr.
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 restarted 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
Mr Watts - the answers
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]
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 patient’s weight)
• Most hospitals will produce dose/Kg protocols for
all their main indications
LMWH
Indication
Enoxaparin
(Clexane)
40mg od
Dalteparin
(Fragmin)
5000iu od
40mg 12hours prior to
operation
40mg for each day postoperative 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
Medical
DVT prophylaxis
Surgical DVT / PE
prophylaxis
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 patient’s INR > 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
A&E department) BUT all patients should be followed up to consider
possible underlying causes.
Heparin Links
• http://www.mja.com.au/public/issues/177_07_07
1002/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_220
506.pdf
British Society for Haematology guidelines for heparin therapy – hot off the
press 2006
• http://www.hscj.ufl.edu/resman/manualpdfs/Hep
arin_Orders_Med_Surg_Crit_Care.pdf
coum
+
ARIN
anticoagulant
= WARFARIN
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 A&E with a ‘torrential’
epistaxis. He is haemodynamically stable but his
INR is 9.9. What is your management?
Warfarin
• The most famous coumarin anticoagulant
(name another!)
• Developed at The Wisconsin Alumni
Research Foundation (
http://www.warf.ws/ - for the nonbelievers!)
• 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)
Warfarin induced skin necrosis
• Main side effect – Increased risk of
bleeding
• Famously causes idiosyncratic skin
necrosis at large doses see …
(http://pathology.uc.edu/LABLINES/V7I6.pdf )
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
Drug Interactions With Warfarin
Drugs that Increase
INR – Increase effect
Drugs that Decrease
INR – Reduce effect
[includes Enzyme inhibitors] [includes Enzyme inducers]
NSAIDs
Omeprazole / Cimetidine
Macrolides
Ciprofloxacin
Phenytoin
Carbamazepine
Rifampicin
Oral Contraceptives
Flu/Ketoconazole
Griseofulvin
Isoniazid
Trimethoprim
Amiodarone / verapamil
Fennerty nomogram
Fennerty 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; 288:1268-70.
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
don’t have to memorise it!)
Warfarin Dosing - II
Day
INR
1st
2nd
< 1.4
< 1.8
1.8
> 1.8
<2.0
2.0-2.1
2.2-2.3
2.4-2.5
2.6-2.7
2.8-2.9
3.0-3.1
3.2-3.3
3.4
3.5
3.6-4.0
>4.0
3rd
Warfarin dose (mg)
10
10
1.0
0.5
10
5
4.5
4
3.5
3
2.5
2
1.5
1.0
0.5
0
Predicted maintenance dose:
4th Day
INR
Warfarin (mg)
<1.4
>8
1.4
8
1.5
7.5
1.6-1.7
7
1.8
6.5
1.9
6
2.0-2.1
5.5
2.2-2.3
5
2.4-2.6
4.5
2.7-3.0
4
3.1-3.5
3.5
3.6-4.0
3
4.1-4.5 Miss out next day's
>4.5
dose, then give 2mg
Miss out 2 days' doses
then give 1mg
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 INR< 4.0
• The risk of haemorrhage is increased by:
- Increasing age > 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.
Bleeding Hell! – What to do about it
•
Major bleeding—stop 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 > 8.0, no bleeding or minor bleeding—stop warfarin, restart when
INR < 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. 0.5–2.5 mg using
the intravenous preparation orally); repeat dose of vitamin K if INR still too
high after 24 hours
•
INR 6.0–8.0, no bleeding or minor bleeding—stop warfarin, restart when
INR < 5.0
•
INR < 6.0 but more than 0.5 units above target value—reduce dose or stop
warfarin, restart when INR < 5.0
•
Unexpected bleeding at therapeutic levels—always investigate possibility of
underlying cause e.g. unsuspected renal or gastro-intestinal tract pathology
British Society for Haematology Guidelines as per BNF 2003
For the Warfarin addicted ….
http://www.acforum.org/doc_education_mana
gement.ppt#316
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/oralanticoa
gulation.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/bak104
41_fm.html#CHDDCIFC
Another excellent overview from our friends down under – good on ya!
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!
Digoxin
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?
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.
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
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
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.
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.
DIGOXIN Challenge
A 78yo man with COPD presents in A&E with a right lower
lobe pneumonia and fast AF.
U+Es: 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
patient’s details for you.
1.Calculate his creatinine clearance
2.Write up the loading and maintenance doses of
digoxin on your charts. You should also write up the
other medications you would give him.
3.List three other investigations he may require.
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 U+Es, Calcium and magnesium, Blood
and sputum cultures
Chest radiograph
ECG
ABGs
When heart rate is improved - Echocardiogram
So just how many did you get?
…and there’s more!
References
• http://www.emedicine.com/med/topic568.h
tm
Recommended review on e.medicine
Insulin and Sliding Scales
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.
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.
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.
What’s 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.
What’s 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.
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.
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
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.
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 don’t get one without the other!
– Potassium should be added to all bags of fluid unless the serum K+
is >5.0mmol/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.
– Don’t stop the sliding scale until the patient is (a) eating and drinking
properly (b) clinically improved.
Example of Insulin sliding scale and infusion
Date
Type of fluid
Volume
Added
Rate
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
>15.1
8.0
Signature
of doctor
Remember: You would also need to write up regular fluids with potassium
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.
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 patient’s meals.
• Although this sounds very didactic in fact it is an educated guestimate of the patient’s
insulin requirements. You may find patient’s 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
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.
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.
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.
Steroid Therapy
Professors Knight and Fowler realised that their ‘hobby’ was getting out of hand!
Challenging Practice
(1) List 5 different routes of administration
for steroid therapy with an indication for
each.
(2) List 3 side effects of long term steroid
therapy.
(3) List 3 contraindications to steroid therapy
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 (<15yo), Pemphigus, AIHA, ITP, Demyelination
NB: Anyone on steroid therapy long term (but not on
replacement therapy) – Don’t forget a Bone Sparing
Agent (BSA)!
‘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. perioperative) – 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
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
>7.5mg/24 hours this will suppress their HypothalamicPituitary-Adrenal [HPA] axis.
• Therefore any patient who presents unwell on replacement
hydrocortisone or on long term prednisolone > 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
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
Unwell Patients and steroids
• If a patient is on long term steroids or has
known Addison’s 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 Addison’s 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.
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
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 Crohn’s 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
Recommended doses
(1)
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?q=%22dexamethasone%22#_hit
Phenytoin
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?
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.
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!’
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 > 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.
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 <
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 < 20 ml/min
Corrected level= Measured phenytoin level
[(albumin x 0.1) + 0.1]
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
Therapeutic Phenytoin levels
10 - 20 mg/l
(Note that reference ranges may vary between laboratories and local reference ranges should be consulted)
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.
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.
Phenytoin Exercise
A 34yo man presents to A&E 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.
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.
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.
References
www.tufts.edu/med/neurosurgery/
• Wonderful image on first phenytoin slide
http://wwwclinpharm.medschl.cam.ac.uk/pages/teaching/ima
ges/
• Excellent clinical pharmacology resource
http://www.bnf.org/BNF/bnf/current/3617.htm
• BNF guide to management of status
epilepticus