Oxford University Hospitals NHS Trust Injectable medicines study day: Claire Waghorn Pharmacist

Kinetics oral vs IV Stability and compatibility Information sources High risk medicines

Why do we use Injectable medicines? If the oral route is unsuitable e.g. NBM If medicines are destroyed by stomach acid e.g. insulin If medicines are not absorbed orally e.g. heparin If the IM route is inappropriate use IV medicines e.g. haemophilia Provides flexibility: To obtain high blood concentrations very quickly For a rapid, continuous response For a slow, continuous infusion, titrated according to response Other examples eg gentamicin

Kinetics: oral dose vs. IV bolus Single IV bolus dose profile

Multiple daily dosing vs. infusions Why would you want to give intermittent infusions eg red man syndrome. Speed shock – if given too quickly Multiple daily dosing at steady state

Kinetics: IV bolus + infusion Which drugs would you want to give loading dose? Why? Profile following a loading dose (bolus) and maintenance infusion

Relationship between plasma level & effect = peak Therapeutic range = trough Narrow therapeutic range – what does it mean? Ask for examples – Theophylline, digoxin, gentamicin. Vancomycin – just do trough levels (see MI bulletin)

Stability of Injectable products After a medicine has been prepared, it starts to degrade. This results in by-products, which may be pharmacologically active, inactive or even toxic. Incompatible medicines may: Block venous access device Introduce an embolus These may reduce the effectiveness of treatment Minimise risks by: Adhere to compatibility information Prepare immediately before use Maximum expiry 24 hours after preparation Prepare before use – injectables SOP Check Embolus definition.

Mechanisms by which medicines degrade pH dependent reactions (acid-alkaline) Photo degradation (light) Concentration dependent precipitation Reaction with water (aqueous solutions) Absorption of medicine by components of drug delivery system pH dependent reactions – just some background wouldn’t expect you to work out if compatible. Most drugs are weak acids – mix with fluids ??

pH Dependent Degradation pH < 7: acidic pH > 7: alkaline Acidic and alkaline medicines or solutions may react with one another Glucose 5% = pH 4-5 Sodium chloride 0.9% = pH 7 Mix like pH with like pH

pH Sensitive medicines- examples Amphotericin = acidic Fungizone brand: glucose 5% 4.2<pH<5.0 Use glucose 5% flushes Phenytoin = alkaline always given in sodium chloride 0.9%, precipitation risk if pH<11.5 Epoprostenol (Flolan), Sodium fusidate (Fucidin), Terlipressin (Glypressin) all come with buffered solution for preparing these medicines: always use it. Insulin comes buffered in solution of pH 7 Phenytoin – needs a filter because of risk of precipitation

Amphotericin and Terlipressin Use the diluent supplied. Don’t give it away unless it is needed.

Photo-degradation Light is energy Promotes chemical reactions May result in degradation Light-sensitive medicines: brown ampoule for storage Usual effect is change in colour e.g. dobutamine turns pink. TPN cover bags to protect fat soluble vitamins Sodium Nitroprusside: Degrades to cyanide products on exposure to light Wrap infusion bag and giving set with foil provided Brown ampoules – vitamins, frusemide Aminophylline – straw coloured to start with.

Emulsions Emulsions are very delicate balance of oil and water. Upsetting this balance can cause cracking or splitting. Identified by milky white appearance. PN, diazepam emulsion, fat soluble vitamins, propofol. Why is there a diazemuls product and a diazepam injection???

Concentration-dependent Precipitation Medicines often poorly soluble in aqueous solution Formulated as salts to increase solubility May require minimum volume of dilution e.g. cotrimoxazole: (75mL glucose 5% or 125ml sodium chloride 0.9% per 5mL ampoule) Precipitation possible at low temp (e.g. mannitol, 20% = supersaturated solution) Calcium salts, magnesium salts, avoid mixing with other medicines, especially phosphates Formulated in polyethylene glycol??? Correcting magnesium and calcium far more these days.

Adsorption by delivery system Medicines may adsorb onto plastic, glass PVC main problem Insulin, glyceryl trinitrate, ciclosporin, isosorbide dinitrate Leeching of phthalate plasticisers (ciclosporin) Low sorption giving sets Non-PVC bags Short expiry times in PVC ? Not a problem with insulin as titrating it to response. Phthalates leached with cyclosporin – not a significant problem.

What can you do to ensure that incompatibilities are avoided? Check if drugs are compatible with the infusion fluid and each other. Unless you have positive proof that they are do not give together. Ideally do not infuse drugs at the same time through the same venous access device. Where several drugs are given through the same device flush well with sodium chloride 0.9% (or glucose 5% if the injectable monograph advises) before, between and after administration to avoid mixing. If any obvious change occurs to a solution DO NOT ADMINISTER IT – ask the pharmacist for advice.

Information sources Local medicines administration procedures Injectable medicine monographs BNF Appendix 6: intravenous additives Product information leaflets (SPC) Clinical Pharmacist on ward Medicines Information department (Ext. 21505) Extravasation Antidotes for different drugs Plastic surgery reg Hydrocortisone inj/cream Diclofenac gel

Pharmacy Intranet site

High alert medicines Increased risk of causing significant patient harm when used in error. Knowing which medicines are high alert – remind you to use additional safety strategies. Injectable examples: amiodarone, chemotherapy, vasoactive agents, heparin, opioids, insulin, opioids Three ways to safeguard therapy: Reduce or eliminate errors e.g. training, ready to administer solution Make errors visible e.g. independent double checks, bar coding Minimise consequences of error e.g. monitoring, antidote prescribed and available. Dalteparin LMWH Heaprin now ready to use Cardiac monitoring for phenytoin. Monitoring with PCAs

National Patient Safety Agency Alerts March 2007 Promoting safer use of injectable medicines– competencies re: preparation, administration and monitoring of injectable medicines March 2007 – competence re: preparing and administering Heparin therapy

Nov 2010 Preventing fatalities from loading doses June 2010 Safer administration of insulin Feb 2010 Injectable medicines in theatres April 2008 Heparin flushes March 2007 Promoting the safer use of injectable medicines May 2006 High dose diamorphine and morphine October 2002 Potassium solutions: risks to patients from errors occurring during intravenous administration

High Alert Medicines Potassium Ampoules -Store in CD cupboard Max rate = 10-20mmol / hour Max peripheral concentration = 40mmol / litre Care with mixing Amiodarone Central administration if repeated doses Max concentration for dilution Phenytoin Cardiac monitoring Filter when administering as an infusion Where are ampoules kept? 10 years ago research – lots of problems. Mix thoroughly but generally use ready made solutions. (with or without pump at 20mmols/L)