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Common Drugs - Dosing and Monitoring Toxic? Me? With My Therapeutic Window? PHENYTOIN.

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Presentation on theme: "Common Drugs - Dosing and Monitoring Toxic? Me? With My Therapeutic Window? PHENYTOIN."— Presentation transcript:

1 Common Drugs - Dosing and Monitoring Toxic? Me? With My Therapeutic Window? PHENYTOIN

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 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 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?

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 >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).

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 <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.

12 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.

13 Gentamicin challenge You are the FY1 doctor on acute medical on-call. The next patient Mrs DB (DOB ) 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?

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 that’s 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 units 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 ) APTT needs to be checked at least once every 24hours after therapeutic level is achieved.

21 A quick calculation … _Crit_Care.pdf _Crit_Care.pdf Mr James Watt is a 43yo man (d.o.b 12/04/63) (hospital number ) 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.

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 patient’s weight) Most hospitals will produce dose/Kg protocols for all their main indications

26 LMWH IndicationEnoxaparin (Clexane) Dalteparin (Fragmin) Medical DVT prophylaxis 40mg od5000iu 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 ACS1mg/kg bd120iu/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 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.

28 Heparin Links 1002/eik10205_fm.htmlhttp://www.mja.com.au/public/issues/177_07_ /eik10205_fm.html Nice summary of LMWH treatment Nice summary of UH treatment (a little technified at the end!) 506.pdfhttp://www.bcshguidelines.com/pdf/heparin_ pdf British Society for Haematology guidelines for heparin therapy – hot off the press arin_Orders_Med_Surg_Crit_Care.pdfhttp://www.hscj.ufl.edu/resman/manualpdfs/Hep arin_Orders_Med_Surg_Crit_Care.pdf

29 + = WARFARIN coum ARIN anticoagulant

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 A&E 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 ( - for the non- believers!) Hence its name W ARFarin 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 … ( ) 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] NSAIDsPhenytoin Omeprazole / CimetidineCarbamazepine MacrolidesRifampicin CiprofloxacinOral Contraceptives Flu/KetoconazoleGriseofulvin Isoniazid Trimethoprim Amiodarone / verapamil aRetrovirals

34 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: 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!)

35 Warfarin Dosing - II DayINR Warfarin dose (mg) Predicted maintenance dose: 4 th Day 1 st < INR Warfarin (mg) 2 nd > rd < Miss out next day's dose, then give 2mg >4.00 >4.5 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 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.

37 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

38 For the Warfarin addicted …. 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. agulation.pdf British Society for Haematology guidelines (2005) on oral anticoagulation – everything you want to know and more! 41_fm.html#CHDDCIFC 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 A&E with a right lower lobe pneumonia and fast AF. U+Es: Na + 141mmol/l, K mmol/l Urea 32.8 mmol/l, Creatinine 140µmol/l. He is guestimated to weigh 60kg. He has no known allergies. The lovely 3 rd 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.

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 U+Es, 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 there’s more!

51 References tmhttp://www.emedicine.com/med/topic568.h tm 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 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.

57 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.

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 InsulinTrade nameDuration of action Superseding Insulin LisproHumalogRapid actingActrapid insulin Insulin aspartNovorapidRapid actingActrapid 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 GlargineLantusLong actingMonotard or ultratard Insulin zinc suspension Humulin L (lente)Long acting Insulin detemirLevemirLong 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 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.

62 Example of Insulin sliding scale and infusion DateType of fluidVolumeAddedRate Signature of doctor Normal saline50ml50 units of Novarapid insulin According to sliding scale Sliding scale Blood glucose Units per Hour 0 – 4.0Zero (Type2 DM) 0.5 (Type1) 4.1 – – – – – – > 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 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

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 – 2/3 rd 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 = 2/3 rds (48u) = 32u; Evening dose 1/3 rd (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 (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

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 (<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)!

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 >7.5mg/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 > 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 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.

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 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

77 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 (2) Prednisolone 40mg PO od for 4 to 6 weeks, then slow reducing dose. Success of treatment judged by reduced ESR and clinical improvement. (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 mg 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.

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 > 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 < 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]

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 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 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 15.9x10 9 /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 Wonderful image on first phenytoin slide clinpharm.medschl.cam.ac.uk/pages/teaching/ima ges/ Excellent clinical pharmacology resource BNF guide to management of status epilepticus


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