19th March 2024

Use of National or Local Guidelines on Appropriate and Safe Prescribing

Safe Prescribing

Safe prescribing of Anticoagulants and Opioids

Anticoagulants, antibiotics, and opioids are commonly prescribed classes of medication in modern medicine. To prescribe these medications, one needs to consider several patient factors such as weight, platelet count and renal/liver function. There are many sources of information for support in prescribing such medications, and these can be divided into two broad categories which include local or national resources. Local resources can include guidelines produced by a hospital trust. Healthcare professionals such as pharmacists and microbiologists also form part of local resources and can help to prescribe appropriately. National resources include the British National Formulary (BNF) and the National Institute of Health and Care Excellence (NICE) guidelines.

Low molecular weight heparin

Some of the most used anticoagulants in modern medical practice include low molecular weight heparins (LMWHs) and vitamin K antagonists (VKAs), which include warfarin. LMWHs act on the final common pathway in the coagulation cascade. In normal physiology, activation of factor Xa will lead to conversion of prothrombin to thrombin. It is thrombin which is involved in converting fibrinogen into fibrin to help form a stable clot. The LMWHs activate antithrombin III which in turn binds to and inhibits factor Xa. As a result, prothrombin is not converted into thrombin and, in turn, fibrinogen is not converted to fibrin which is needed for clot formation. The LMWHs are cleared mainly by the renal system so must be cautiously prescribed in patients with renal failure. LMWHs are contraindicated in low platelet levels and local guidelines can give more information on when to suspend LMWHs when there is thrombocytopenia. Monitoring is not often required when LMWHs are prescribed. However, if needed, anti-Xa levels are used for monitoring. The reversal agent for LMWHs is protamine sulfate. The main adverse effect of LMWHs is bleeding. Less common adverse effects include osteoporosis, spontaneous fractures, hypoaldosteronism. Heparin-induced thrombocytopenia (HIT) is a potentially devastating adverse effect where there is the development of antibodies against the heparin/platelet factor 4 complex. This leads to platelet activation, resulting in thrombocytopenia, but can also paradoxically cause potentially fatal arterial and venous thromboses. Part of the management would include switching to an alternative anticoagulant.

Warfarin

Warfarin competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1), an essential enzyme for activating vitamin K. It is vitamin K which is needed for the synthesis of clotting factors II, VII, IX and X as well as both proteins C and S. Therefore, if vitamin K levels are reduced the production of these clotting factors and proteins will be reduced leading to less clot formation. Warfarin is mainly excreted via the kidneys. Hence, prescribe cautiously in patients with renal dysfunction. Warfarin is monitored via INR. It is important to note that in the first few days of initiating warfarin therapy, it is prothrombotic, and hence, bridging therapy with LMWHs might be needed. In patients who have life-threatening haemorrhage or those with intracranial bleeding and on warfarin Prothrombin complex concentrate (PCC) can be used to rapidly reverse the anticoagulant effects. PCC is a plasma derived concentrate of vitamin K dependent clotting factors and proteins. Warfarin adverse effects include bleeding, purple toes and skin necrosis. Skin necrosis occurs as protein C production is reduced in the first few days of administration, leading to a prothrombotic state and thrombosis in venules. Warfarin can cross the placenta and has teratogenic properties. It is advised that warfarin be suspended during pregnancy and especially during the first and third trimesters. Patients on warfarin also need to be aware that certain foods can either inhibit or increase the anticoagulant effect of warfarin. For example, foods such as kale, green tea leaves, Brussel sprouts, and spinach contain vitamin K which can inhibit the anticoagulant effects of warfarin. Conversely, grapefruit juice and increased alcohol intake can increase the anticoagulant effects of warfarin.

Opioids

Opioids are widely used for analgesia in both palliative and non-palliative care settings. Patients who are approaching the end of their life may need additional opioids to control breakthrough pain (BTP). It is defined as an episode of severe exacerbation of longstanding pain in patients who have chronic conditions such as cancer. BTP doses are calculated as typically 1/10 to 1/6 of the total daily regular dose of opioids. There might be cases where the route of administration may need to be altered. For example, a patient who is at high risk of aspiration may need opioids administered subcutaneously.

Oral Route	Subcutaneous Route	Calculation
Oral morphine	Subcutaneous morphine	Divide by 2
Oral morphine	Subcutaneous diamorphine	Divide by 3
Oral oxycodone	Subcutaneous diamorphine	Divide by 1.5

References

Solari F, Varacallo M. Low Molecular Weight Heparin (LMWH) Updated 2022 Jul 19. In: StatPearls Internet. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK525957/
Patel S, Singh R, Preuss CV, et al. Warfarin. Updated 2022 Mar 13. In: StatPearls Internet. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470313/
British National Formulary. (2022) Prescribing in palliative care. Online Available from: https://bnf.nice.org.uk/medicines-guidance/prescribing-in-palliative-care/
National Institute of Health and Care Excellence. (2015) Blood transfusion. https://www.nice.org.uk/guidance/ng24/resources/blood-transfusion-pdf-1837331897029

Prescribing guidelines

Anaphylaxis

Anaphylaxis is a systemic IgE-mediated hypersensitivity reaction which results in life-threatening airway and circulatory problems after exposure to an allergen. It is caused by release of inflammatory mediators after degranulation of basophils and mast cells. The initial management is IM adrenaline and in adults the concentration is 1mg/mL (1:1000) concentration. The intramuscular dose of adrenaline is 500 micrograms (0.5mL). Anaphylactic reactions may be confirmed by measuring mast cell tryptase levels. Ideally, three samples should be taken. These should be taken as soon as feasible after suspected anaphylaxis (but do not delay treatment to measure tryptase levels), 1–2 hours (but no later than 4 h) after onset of symptoms and at least 24 hours after complete resolution or in convalescence.

Cardiac arrest

In cardiac arrests, certain drugs are given at specific times depending on whether you are on the shockable or non-shockable side of the cardiac arrest management algorithm. When managing non-shockable rhythms, adrenaline 1mg IV/IO (concentration 1:10000) should be given as soon as a non-shockable rhythm is recognised on the defibrillator. It should then be given every alternate cycle. In shockable rhythms, adrenaline 1mg IV/IO (concentration 1:10000) should be given after the third shock. Once the first dose of adrenaline is given, further doses should be given every 3-5 minutes. Amiodarone 300mg IV/IO should be given after 3 shocks. A further dose of 150mg IV/IO should be considered after 5 shocks.

Diabetic Emergencies

Hypoglycaemia

Conscious patients who can swallow should be treated with oral fast-acting carbohydrates such as glucose tablets, Glucogel® or pure fruit juice. Once the blood glucose levels normalise, then a long-acting carbohydrate should be given to prevent blood glucose levels from falling again. This can include two biscuits or a slice of bread. In patients who are unconscious and hypoglycaemic, then either 200mls of 10% IV glucose or 100mls of 20% IV glucose should be given over 15 minutes. If intravenous access is not feasible, then 1mg of IM glucagon can be given.

Diabetic ketoacidosis

Patients who have diabetic ketoacidosis (DKA) require strict fluid resuscitation. If the systolic blood pressure (SBP) is below 90mmHg, then 500mls of 0.9% sodium chloride should be infused over 10-15 minutes. This should be repeated if SBP remains below 90mmHg. If it becomes difficult to raise the SBP, then consider contacting the critical care team. Once the SBP is above 90mmHg then infuse 1L of 0.9% sodium chloride over 1 hour. As an example, subsequent fluid administration can be as follows:

0.9% sodium chloride 1L with potassium chloride over the next 2 hours
0.9% sodium chloride 1L with potassium chloride over the next 2 hours
0.9% sodium chloride 1L with potassium chloride over the next 4 hours
0.9% sodium chloride 1L with potassium chloride over the next 4 hours
0.9% sodium chloride 1L with potassium chloride over the next 6 hours

The fixed-rate intravenous insulin infusion (FRII) is calculated as 0.1 units/kg/hour. Once the glucose drops to <14 mmol/L, then in addition to adding a 10% dextrose infusion, consider reducing the rate of intravenous insulin infusion to 0.05 units/kg/hr to avoid the risk of developing hypoglycaemia and hypokalaemia.

Hyperglycaemic hyperosmolar state

The hyperglycaemic hyperosmolar state (HHS) is a life-threatening metabolic decompensation of diabetes which presents with severe hyperglycaemia and profound dehydration, typically accompanied by alteration in consciousness ranging from lethargy to coma. It usually presents with those with Type 2 diabetes mellitus (T2DM). Unlike DKA, it usually does not present with significant hyperketonaemia or acidosis, but this may not always be the case. It usually presents in those over 45 years but it is known to present in younger groups of patients. The predominant cause of HHS is either a chest or urinary tract infection. HHS has a high mortality because it may be due to, or complicated by, vascular events such as myocardial infarction, stroke or peripheral arterial thrombosis. The aims of treatment are to normalise blood glucose levels, normalise osmolality and replace fluid and electrolyte losses.

The main type of fluid used in treating HHS is 0.9% sodium chloride. Only switch to 0.45% sodium chloride solution if the osmolality is not declining despite adequate positive fluid balance. The fall in osmolality should not be more than 3.0-8.0 mOsm/kg/hr. The fall in glucose should not be more than 5.0 mmol/L/hr. Insulin infusions should be commenced in the following situations:

If there is HHS and ketonaemia (blood ketones 3ß-hydroxybutyrate >1.0 – ≤3.0
mmol/L or urine ketones < 2+) and not acidotic (venous pH >7.3 and bicarbonate
>15.0 mmol/L) then use 0.05 units/kg/hr OR
If there is significant ketonaemia (3ß-hydroxybutyrate >3.0 mmol/L) or ketonuria
(≥ 2+) with a pH <7.3 and bicarbonate <15 /mmoL, then use the DKA guidelines at 0.1 units/kg/hr

The underlying precipitant of HHS should be identified and treated.