Oxford Handbook of Practical Drug Therapy (2 edn)
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Blood, blood products, and anaemia
Drugs and anaemia BNF 9.1 598
Blood transfusion 600
Factor VIII and related products BNF 2.11 604
Erythropoietin and analogues BNF 9.1.3 608
Colony stimulating factors BNF 9.1.6 612
Iron salts BNF 9.1.1 614
Folic acid and folinic acid BNF 9.1.2 and 8.1 618
Vitamin B12 BNF 9.1.2 620
Desferrioxamine (deferoxamine) BNF 9.1.3 622
Blood, blood products, and anaemia: Drugs and anaemia BNF 9.1
Drugs are used to treat anaemia, but can also be responsible for it. Fig. 9.1 offers a general guide. See individual articles for more information.
Drugs and anaemia
Blood, blood products, and anaemia: Blood transfusion
| Blood group | Antigen on erythrocytes | Antibodies in plasma |
|---|---|---|
O A B AB | None A B AB | Anti-A and anti-B Anti-B Anti-A None |
| Blood group | Antigen on erythrocytes | Antibodies in plasma |
|---|---|---|
O A B AB | None A B AB | Anti-A and anti-B Anti-B Anti-A None |
See 
immunoglobulins p. 721 for information on prevention of rhesus disease of the newborn.
Potential uses
Treatment of blood loss and severe anaemia.
Contraindications and cautions
Do not use blood indiscriminately. It should not be given for mild or asymptomatic anaemia, or to ‘normalize the numbers’.
There are several ways in which the need for blood can be reduced:
Checking for and correcting anaemia before elective surgery.
Careful use of anticoagulant drugs in the perisurgical period (see Warfarin, p. 124 for guidance).
Sometimes stimulating erythropoiesis with erythropoietin is more appropriate than blood transfusion.
Blood can affect the body’s immunological response to a renal transplant; only give blood when it is essential, and after consulting an expert.
Patients with haematological malignancies have special requirements for blood and blood products (e.g. leucocyte depleted, CMV-negative); always seek haematological advice before giving a transfusion to such patients.
In the UK, blood is screened for HIV, HTLV (human T-cell lymphotropic virus), and hepatitis B and C, but the presence of other, as yet unidentified viruses cannot be excluded.
How to use
Practical considerations
For more information consult the Handbook of Transfusion Medicine (
http://www.transfusionguidelines.org.uk).
Record the reason for the transfusion in the notes. Obtain the patient’s consent for transfusion. It is prudent to record this formally using a consent form.
Prescribe the blood on the infusion section of the drug chart. Do not use a circle with a dot inside to indicate a unit; this can be confused with a zero.
Crossmatching
Samples for crossmatching blood require special handling:
To avoid mixing samples, only take blood for crossmatching from one patient at a time.
Write the patient’s details on the tube by hand (do not use addressograph labels).
Many hospitals require an additional method of linking the patient to the sample (e.g. a red label system).
Take time to complete the crossmatching form as completely as possible.
It is very important to advise the laboratory if any atypical antibodies have been identified, as this will complicate the crossmatching procedure.
Telephone the laboratory if the sample is urgent; if the blood is required at a specific time (e.g. for a surgical procedure), ensure that this is clearly stated, especially if it is not for several days.
Make sure that you request a suitable amount of blood; check your local protocol for elective surgical cases.
If the patient has already had a blood transfusion more >3 days before or there has been a significant delay since the initial sample was taken, a second crossmatch sample may be required.
Transfusion
Procedures for transfusion should be performed carefully, in order to avoid serious hazards; this is best summarized as giving the right blood, to the right patient, at the right time, in the right place.
Identify the patient. Use the wristband, but if the patient can speak also check with them.
Confirm that the name, date of birth, hospital number, and sex are correct on the blood unit.
Check that the blood compatibility information (ABO and rhesus groups) and unique blood unit donation number are correct on the blood unit and the form sent with the blood.
On some occasions the blood group may not be the same as the patient’s group; check that it is still compatible (e.g. A group blood for an AB patient). If you are at all unsure, speak to the blood bank.
Check that the blood matches any special requirements (e.g. gamma-irradiated, CMV-seronegative).
Perform all these checks at the bedside, and put up the infusion immediately.
The use of barcodes avoids all of this.
Check the physical state of the unit of blood; do not infuse it if it looks damaged or abnormal in any way.
Blood should be infused though a dedicated (large-bore) cannula.
Do not add anything to, or infuse anything through, the same cannula as blood; this includes drugs, which should not be added to blood infusion bags.
A unit of blood should be completely infused within 4 hours.
Most common and most serious adverse effects
Acute, severe reactions
These are most common within the first 15 minutes of the infusion. Four main types are recognized:
Acute haemolytic transfusion reactions; these should be avoided if the procedures previously listed are followed.
Infusion of a bacterially contaminated unit.
Transfusion-associated acute lung injury (TRALI); this is usually the result of an interaction between donor plasma antibodies and recipient leucocytes.
Severe allergic reactions or anaphylaxis; these are more common when products containing large volumes of plasma are given.
Treatment of severe reactions is supportive. Stop the infusion. Treat anaphylaxis (see Adrenoceptor agonists, p. 218 ). Summon senior help and notify the blood bank.
Febrile and non-haemolytic transfusion reactions
These occur in about 1–2% of patients and are probably due to donor leucocytes. They tend to occur towards the end of the transfusion.
Fever (>1.5°C above baseline) and rigors are the cardinal signs; this may represent a severe reaction, so monitor the patient closely, but in most cases it will not progress. The symptoms can be relieved by:
Slowing the rate of infusion.
Paracetamol for the fever.
Chlorphenamine (an antihistamine) for urticaria.
Intravenous steroids are not usually necessary; seek expert advice if the patient has a history of febrile reactions to transfusion.
Fluid overload
Patients with chronic anaemia and cardiac disease are usually euvolaemic or hypervolaemic, and blood transfusion can precipitate pulmonary oedema (transfusion-associated circulatory overload). If blood transfusion is essential, the risk of fluid overload can be reduced by:
Giving no more than 1 unit in each 12-hour period (over 4 hours during that period).
Giving furosemide 20 mg intravenously before each unit.
Delayed reactions
These are rare, but can be life threatening; seek expert advice.
Delayed haemolysis due to red cell antibodies other than ABO.
Transfusion GVHD.
Iron overload after repeated transfusions (see Desferrioxamine, p. 622 ).
Post-transfusion purpura (thrombocytopenia).
Major drug-drug interactions
Blood is incompatible with almost all other drugs and infusion solutions. Give blood via a dedicated cannula and do not add drugs to units of blood.
Monitoring
Safety and efficacy
Ensure that you have a sound indication for blood transfusion.
Severe reactions are most common within 15 minutes of the start of the infusion.
Before starting transfusion, record BP, pulse, and temperature
Check the pulse and temperature 15 minutes after starting the transfusion.
Observe the patient throughout the transfusion.
Repeat the BP, pulse, and temperature measurements when the transfusion is completed.
If the patient is conscious, further recordings are not needed unless the patient becomes unwell or has symptoms and signs of a reaction.
An unconscious patient should have their pulse and temperature measured at intervals during the transfusion.
Patient information
Objection to blood transfusion is not restricted to patients who are Jehovah’s Witnesses. Always obtain consent for blood transfusion.
Warn patients that a transfusion may be required if you are assessing them before major surgery.
Prescribing information: Blood transfusion
Prescribe blood on the dedicated blood products section or infusion section of the drug chart.
Blood, blood products, and anaemia: Factor VIII and related products BNF 2.11
Clotting factor
Antithrombin III concentrate: used for congenital deficiency of antithrombin III.
Factor VIIa: recombinant product for patients with inhibitors of factors VIII and IX.
Factor VIII inhibitor bypassing fraction: for patients with inhibitors of factor VIII.
Factor IX: used for patients with haemophilia B.
Factor XIII: used for congenital deficiency of factor XIII.
Protein C concentrate: for patients with protein C deficiency.
Potential uses
Treatment and prophylaxis of bleeding in patients with haemophilia A.
Contraindications and cautions
These peptide coagulation factors can induce the formation of inhibitory antibodies, which can render clotting factors ineffective.
| Degree of haemorrhage/type of surgical procedure | Factor VIII conc. required (%) (IU/dL) | Example dose for a 70-kg patient (units) | Regimen |
|---|---|---|---|
Haemorrhage | |||
Early haemarthrosis, muscle bleed, or oral bleed | 20–40 | 1000 | Repeat every 12–24 hours. Give for at least 1 day or until the bleeding episode has resolved |
More extensive haemarthrosis, muscle bleed or haematoma | 30–60 | 1500 | Repeat infusion every 12–24 hours for 3–4 days or more until pain and disability have resolved |
Life-threatening bleeds, e.g. intracranial or abdominal | 60–100 | 2800 | Repeat infusion every 8–24 hours until the threat is resolved |
Surgery | |||
Minor, including tooth extraction | 30–60 | 1500 | Repeat every 24 hours. Give for at least 1 day or until the bleeding episode has resolved |
Major | 80–100 | 3000 | Repeat infusion every 8–24 hours until adequate |
| Degree of haemorrhage/type of surgical procedure | Factor VIII conc. required (%) (IU/dL) | Example dose for a 70-kg patient (units) | Regimen |
|---|---|---|---|
Haemorrhage | |||
Early haemarthrosis, muscle bleed, or oral bleed | 20–40 | 1000 | Repeat every 12–24 hours. Give for at least 1 day or until the bleeding episode has resolved |
More extensive haemarthrosis, muscle bleed or haematoma | 30–60 | 1500 | Repeat infusion every 12–24 hours for 3–4 days or more until pain and disability have resolved |
Life-threatening bleeds, e.g. intracranial or abdominal | 60–100 | 2800 | Repeat infusion every 8–24 hours until the threat is resolved |
Surgery | |||
Minor, including tooth extraction | 30–60 | 1500 | Repeat every 24 hours. Give for at least 1 day or until the bleeding episode has resolved |
Major | 80–100 | 3000 | Repeat infusion every 8–24 hours until adequate |
How to use
The treatment of haemophilia should be under the direction of a specialist.
Guidance from the United Kingdom Haemophilia Centre Directors Organisation Executive Committee is available at http://www.ukhcdo.org.
The dose and frequency of administration of factor VIII varies greatly between individuals. Always seek expert advice if a patient with haemophilia is admitted under your care.
The following is offered as a guide only.
The dose can be calculated using the following formula:
Patients with haemophilia should be immunized against hepatitis A and B.
Recombinant factor VIII is very expensive and may not be available to all those who may benefit from it.
If the patient has mild disease consider treatment with desmopressin (see Vasopressin, p. 550 ).
Do not give patients with haemophilia intramuscular injections because of the risk of haematoma.
Most common and most serious adverse effects
These factors are peptides; they can cause allergic reactions (including anaphylaxis).
Haemolysis has been associated with the administration of large doses of these drugs to patients with blood groups A, B, and AB.
Less pure fractions contain fibrinogen, which can build up. This is less of a problem with recombinant products.
Major drug-drug interactions
These patients should not normally be given drugs that increase their risk of bleeding: warfarin, antiplatelet drugs, corticosteroids.
Monitoring
Safety and efficacy
Measure the factor VIII concentration. Liaise with your laboratory about the practicalities of doing this before you send the sample.
Patient information
Patients with haemophilia need to be taught how to identify and avoid injury (especially to joints).
Prescribing information: Factor VIII and related products
This is a specialized area of practice. Liaise with your local haemophilia centre.
Identify whether the bleeding is the result of:
Deficient clotting:
Platelet factors:
Specific deficiency (rare).
Consumption (e.g. disseminated intravascular coagulation and severe haemorrhage).
Antiplatelet drugs.
Treat the underlying cause whenever possible.
Treat the bleeding locally whenever possible (e.g. endoscopic intervention).
Fresh frozen plasma contains clotting factors and can be used if clotting factors are deficient. You will need to know the patient’s blood group.
Remember to include the volume of any blood products in your calculations of fluid balance.
The following drugs are used in special circumstances.
Tranexamic acid
This is an inhibitor of the activation of plasminogen to plasmin. It is used short term for haemorrhage or if there is a risk of haemorrhage in increased fibrinolysis or fibrinogenolysis. Local fibrinolysis occurs in the following conditions:
Prostatectomy and bladder surgery.
Menorrhagia.
Epistaxis.
Conization of the cervix.
Traumatic hyphaema.
Hereditary angio-oedema (danazol or stanozolol are preferred).
Management of dental extraction in patients with haemophilia.
Tranexamic acid is renally excreted; halve the dose in moderate renal insufficiency and give one-quarter of the usual dose in severe renal insufficiency. Do not give during pregnancy. Tranexamic acid can cause thromboembolism, but this is rare.
Etamsylate
This corrects abnormal platelet adhesion (with a normal number of platelets) and is used occasionally for menorrhagia and periventricular haemorrhage in neonates.
Blood, blood products, and anaemia: Erythropoietin and analogues BNF 9.1.3
Recombinant analogues of the endogenous peptide erythropoietin
Erythropoietin is the endogenous hormone. Epoetins are forms of recombinant human erythropoietin.
Epoetin alpha
Epoetin beta
These drugs are clinically indistinguishable.
Epoetin delta
Biosimilars of epoetin alfa (see p. 6 for explanation of biosimilars)
Darbepoetin
This drug has a longer half-life than epoetin.
Methoxypolyethylene glycol-epoetin beta (pegzerepoetin alfa). A continuous erythropoietin receptor activator. It has a longer duration of action than epoetin.
Potential uses
When stimulation of erythropoiesis is required.
Treatment of the anaemia associated with chronic renal insufficiency.
To reduce the duration of the period of anaemia following treatment with cytotoxic chemotherapy.
To increase the yield of autologous blood from healthy donors in a predonation programme.
Contraindications and cautions
These drugs increase the haematocrit; this can precipitate or worsen heart failure.
Do not give them to patients who have recently had a myocardial infarction.
Use of these drugs is associated with a consistent, unexplained excess mortality and increased risk of tumour progression in patients with cancer.
In some cases their use may still be appropriate.
Consider the degree of anaemia, tumour type, and patient prognosis before giving these drugs.
Blood transfusion may be more appropriate for those with advanced or metastatic disease with a good prognosis.
Avoid them in patients with severe or uncontrolled hypertension.
There is no evidence of harm from epoetin during pregnancy, but use it only when the benefits are clear.
No dosage adjustment is usually required in hepatic insufficiency.
Chronic renal insufficiency is one of the major indications for the use of these drugs.
See later notes on actions in the case of pure red cell aplasia.
How to use
Chronic renal insufficiency
Patients with chronic renal insufficiency may be anaemic for several reasons, only one of which is inadequate erythropoietin production.
Always exclude anaemia due to iron, folate, or vitamin B12 deficiency before giving epoetin.
Aluminium toxicity will reduce the efficacy of epoetin treatment (see Desferrioxamine, p. 622 ).
Do not give epoetin by subcutaneous injection for long-term use; give it by intravenous injection.
The target haemoglobin concentration is 10–12 g/dL.
Adjust the dose and frequency of administration to achieve this.
Darbepoetin has a longer duration of action; it can be given once weekly.
Chemotherapy
NICE have recommended that epoetin should not be used routinely in the management of cancer treatment-induced anaemia. It may be considered in combination with intravenous iron for:
Women receiving platinum-based chemotherapy for ovarian cancer with symptomatic anaemia.
Patients who cannot be given blood transfusions and who have profound treatment-related anaemia that is likely to improve survival when treated.
This is an expensive treatment and the benefit needs to be weighed against the cost.
Epoetin can be given by the subcutaneous route for these indications.
Predonation programmes
Patients can donate blood before an operation during which it is expected that blood transfusion will be required. Epoetin treatment can increase the yield.
Pay particular attention to the cautions previously discussed when assessing whether the patient will benefit. This procedure is not widespread in the UK; seek specialist guidance.
Most common and most serious adverse effects
Epoetin is usually well tolerated.
Epoetin causes a dose-dependent increase in BP; if not properly monitored it can cause hypertensive encephalopathy.
Epoetin can also increase the platelet count, although thrombocytosis is uncommon.
Epoetin can, very rarely, cause pure red cell aplasia.
The CSM has advised that, if this occurs, epoetin should be withdrawn and that patients should not be switched to another member of the class.
Major drug-drug interactions
The antihypertensive action of ACE inhibitors and angiotensin receptor blockers is antagonized by these drugs. This is important, because patients with chronic renal insufficiency are commonly given these drugs.
The risk of hyperkalaemia is increased when ACE inhibitors or angiotensin receptor blockers are given concomitantly with epoetin.
Monitoring
Efficacy
Overcorrection of haemoglobin concentration is associated with excess cardiovascular morbidity/mortality.
The target haemoglobin concentration is 10–12 g/dL. If it rises above 13 g/dL, suspend treatment. If the haemoglobin has not risen by at least 1 g/dL after 8 weeks treatment, withhold the drug.
Safety
Measure the BP frequently; this should form part of the routine follow-up of patients with chronic renal insufficiency.
Patient information
Explain that this treatment may make the patient feel better, but that it will not have any effect on the long-term outcome of their disease (renal failure or tumour).
Prescribing information: Epoetin analogues
Dosage regimens are complex and require adjustment according to the indication and individual requirements. Use your local protocol. The following is given as an example. Epoetin alfa and epoetin beta are indistinguishable in their effects, but you must specify in the prescription which one you want to be used, since the doses are slightly different.
Epoetin alfa
Chronic renal insufficiency
By intravenous injection, 50 units/kg 3 times weekly.
Can be increased by 25 units/kg 3 times weekly every 4 weeks to achieve the desired haemoglobin concentration.
Usual dose 25–100 units/kg 3 times weekly.
Cancer chemotherapy
By subcutaneous injection, 150 units/kg 3 times weekly.
Can be increased to 300 units/kg 3 times weekly if required.
Epoetin beta
Chronic renal insufficiency
By intravenous injection, 20 units/kg 3 times weekly.
Can be increased by 20 units/kg 3 times weekly every 4 weeks to achieve the desired haemoglobin concentration.
Blood, blood products, and anaemia: Colony stimulating factors BNF 9.1.6
Recombinant analogues of the endogenous peptide colony stimulating factors
Recombinant human granulocyte colony stimulating factor (rG-CSF); filgrastim
Pegfilgrastim is a polyethylene glycol-conjugated (‘pegylated’) derivative of filgrastim; pegylation increases the duration of filgrastim activity.
Glycosylated recombinant human granulocyte colony stimulating factor (rHuG-CSF); lenograstim
Recombinant granulocyte-macrophage colony stimulating factor (GM-CSF); molgramostim *
Molgramostim stimulates a wider range of cell lines and is associated with a higher incidence of adverse effects.
This drug, which is not a colony stimulating factor, can be used to reduce the neutropenia caused by treatment with cyclophosphamide or platinum compounds.
It is thought to act by selectively protecting normal tissues from the actions of cytotoxic drugs. Its place in chemotherapy regimens is not yet fully established.
Potential uses
When stimulation of neutrophil production is required.
To reduce the duration of the period of neutropenia due to cytotoxic chemotherapy.
To increase the yield of autologous stem and progenitor cells for autologous or allogenic donation.
Treatment of congenital/cyclic/idiopathic neutropenia.
Note that molgramostim is ineffective in congenital neutropenia.
Treatment of persistent neutropenia in patients with HIV infection.
Contraindications and cautions
Take care if the patient has abnormalities of the myeloid line.
For example, molgramostim is contraindicated in myeloid malignancy.
G-CSF can cause myelodysplastic syndromes in patients with severe congenital neutropenia.
Also avoid these drugs if the patient has Kostmann’s syndrome (reduced neutrophils with abnormal cytogenetics).
There is no evidence of harm from these drugs during pregnancy, but use only when essential.
No dosage adjustment is usually required in hepatic or renal insufficiency.
Do not give these drugs 24 hours before, or 24 hours after, a dose of chemotherapy.
How to use
Colony stimulating factors should only be used by specialists experienced in their use.
They will reduce the duration of neutropenia after bone marrow transplant or cytotoxic chemotherapy, but have not been shown to affect overall survival.
They have not been shown to reduce the incidence of fever or infection.
Colony stimulating factors are very expensive; the potential benefits (e.g. earlier discharge from hospital) must be weighed against this. Follow your local guidance.
Always ensure that you know why the patient is neutropenic. Seek specialist help with investigation if the cause is not clear.
Most common and most serious adverse effects
The most common adverse effect is bone pain.
This occurs in about 13% of patients given G-CSF and 45% of patients given GM-CSF.
Colony stimulating factors can cause a leucocytosis, but this is rare. Stop the drug if it occurs.
Colony stimulating factors can cause thrombocytopenia. Measure the platelet count frequently and withdraw the drug if it becomes severe.
Colony stimulating factors can cause splenic enlargement, especially in patients with sickle cell disease.
Hypersensitivity reactions are more common after intravenous infusion.
These drugs can cause a rash; it is more common with molgramostim.
Major drug-drug interactions
There are a few reports that filgrastim reduces the efficacy of fluorouracil.
Monitoring
Safety and efficacy
Patients with neutropenia should have frequent blood counts (usually daily). Neutropenia is usually defined as a neutrophil count <0.5 × 109/L. The target neutrophil count varies with indication; seek specialist advice.
Chemotherapeutic regimens vary in the time when the neutrophil count is lowest; ensure that your treatment regimen covers this period.
Make sure that you also look at the other elements of the blood count, in particular the lymphocyte and platelet counts.
While the neutropenia persists, measure the patient’s temperature 4 times daily and ask about symptoms of infection.
Patient information
Explain that this treatment may allow the patient to go home earlier, but that it will not have any effect on the long-term outcome of the disease.
Advise the patient to report any symptoms of fever immediately.
Prescribing information: Colony stimulating factors
Dosage regimens are complex and require adjustment according to the indication and individual requirements. Use your local protocol. The following is given as an example.
Filgrastim—cytotoxic drug–induced neutropenia
By intravenous or subcutaneous injection, 500 000 units/kg daily.
Do not start within 24 hours of administration of a cytotoxic drug.
The duration of treatment is usually 14 days, but it may be up to 38 days in acute myeloid leukaemia. Follow your local protocol.
Blood, blood products, and anaemia: Iron salts BNF 9.1.1
Essential element
See Desferrioxamine, p. 622 .
See box, p. 617 .
Potential uses
Treatment and prevention of iron deficiency.
Contraindications and cautions
Iron salts, given by mouth, can worsen inflammatory bowel disease.
Avoid oral iron therapy in patients with strictures and diverticula.
Parenteral iron therapy is rarely justified (see following notes) and should not be given to patients with severe hepatic or renal insufficiency.
Allergic reactions to parenteral iron are common; avoid this route if the patient has a history of coeliac disease, asthma, or hypersensitivity to any drugs.
Routine iron supplementation during pregnancy is not justified.
Consider it for women with identified deficiency or risk factors (poor diet and after subtotal or total gastrectomy).
How to use
Administration of iron by the parenteral route is only justified if the patient has:
Failed oral therapy owing to poor adherence.
Severe gastrointestinal adverse effects (see following notes for ways to minimize these).
Continuing severe blood loss.
Malabsorption.
Renal failure and is receiving haemodialysis (or in some cases peritoneal dialysis).
Administration of iron by the parenteral route significantly improves the rate of increase of haemoglobin. However, if the patient needs a very rapid increase in haemoglobin, consider a blood transfusion instead.
Ascorbic acid (vitamin C) increases the absorption of oral iron, but has not been shown to improve the overall clinical response. Combination tablets containing ascorbic acid are more expensive and are not normally justified.
Modified-release formulations are better tolerated, but the iron is released beyond the first part of the duodenum, so absorption may be reduced; they are not recommended.
There is no justification for iron therapy in combination with multivitamins. Combination formulations of iron and folic acid can be used in pregnancy, if both are required.
You should aim to give the patient the equivalent of 100–200 mg of elemental iron daily. The amount of elemental iron varies with different formulations and salts. Table 9.2 is provided in the prescribing section, as a guide.
Treat the cause of the iron deficiency whenever possible (blood loss, poor diet).
| Iron salt | Amount of iron salt per tablet | Content of elemental iron per tablet | Usual daily dose for treatment of iron deficiency |
|---|---|---|---|
Dried ferrous sulphate | 200 mg | 65 mg | 200 mg tds |
Ferrous gluconate | 300 mg | 35 mg | 4–6 tablets daily, in divided doses, before food |
Ferrous fumarate (Fersaday®) | 322 mg | 100 mg | 1 tablet bd |
Ferrous fumarate (Fersamal®) | 210 mg | 68 mg | 1 tablet tds |
Ferrous fumarate (Galfer®) | 305 mg | 100 mg | 1 capsule bd |
| Iron salt | Amount of iron salt per tablet | Content of elemental iron per tablet | Usual daily dose for treatment of iron deficiency |
|---|---|---|---|
Dried ferrous sulphate | 200 mg | 65 mg | 200 mg tds |
Ferrous gluconate | 300 mg | 35 mg | 4–6 tablets daily, in divided doses, before food |
Ferrous fumarate (Fersaday®) | 322 mg | 100 mg | 1 tablet bd |
Ferrous fumarate (Fersamal®) | 210 mg | 68 mg | 1 tablet tds |
Ferrous fumarate (Galfer®) | 305 mg | 100 mg | 1 capsule bd |
Most common and most serious adverse effects
Nausea and vomiting are common.
Constipation is common; diarrhoea can also occur.
Elemental iron is thought to be responsible for these effects; no iron salt is less irritant than another (at equivalent dosages).
Iron salts make the faeces black. This can be mistaken for melaena, but it smells different and is negative on testing for occult blood.
Parenteral iron can cause severe allergic reactions, a metallic taste in the mouth, hypotension, bradycardia, abdominal pain, lymph node enlargement, and arthralgia.
Hypotension is common (5% of patients) with intravenous iron.
Intravenous iron can cause thrombophlebitis. Intramuscular injection of iron can stain the skin. The fear that intramuscular iron can cause muscle sarcoma has not been substantiated.
Major drug-drug interactions
Iron salts form chelates with some other drugs. This reduces the absorption of these drugs. Those most affected include: tetracyclines, quinolones, penicillamine, and levodopa.
Magnesium trisilicate, an antacid, reduces the absorption of oral iron.
Monitoring
Safety and efficacy
The haemoglobin should rise by 1–2 g over 3–4 weeks. Look for causes if it does not (e.g. poor adherence to therapy due to adverse effects, continuing blood loss).
Continue iron therapy for 3 months after the haemoglobin is normal, to replace the body’s stores.
Atrophic glossitis and koilonychia improve, but can take a long time.
Patient information
Make sure that the patient knows that iron therapy takes time to increase the haemoglobin; improvement will be gradual.
Warn the patient that iron salts turn the faeces black.
Keep iron tablets away from children. Iron poisoning in children can be fatal.
Prescribing information: Iron salts
Oral iron
Modified-release formulations and those containing ascorbic acid are not recommended (see earlier notes).
The usual oral dose of elemental iron for treating iron deficiency is 100–200 mg daily.
The dose can be halved for prophylactic treatment (prophylaxis is justified in only a few patients).
The dose may need to be increased by 50% for patients with chronic renal insufficiency.
The usual iron salt used is dried ferrous sulfate. Table 9.2 gives the suggested daily dosages for this and the other commonly prescribed iron salts.
Parenteral iron
Giving iron by a parenteral route is rarely justified (see earlier notes).
Calculate the total body iron deficit as follows:
Example: a 50-kg woman with a haemoglobin of 8 g/dL (normal 14 g/dL) has a deficit of 50 × (14 − 8) × 2.21 = 663 mg. She will require this plus an extra 500 mg (for stores).
By intravenous infusion
Give a test dose first.
Iron dextran contains iron 50 mg/mL. Maximum daily dose 20 mg/kg. Test dose 25 mg.
Iron sucrose contains iron 20 mg/mL. Test dose 50 mg. Usual dosage regimen for haemodialysis patients:
100 mg 1–3 times per week, over sequential dialysis sessions, to a cumulative dose of 1000 mg.
Can be repeated if required.
By intramuscular injection
Iron dextran is licensed for use by intramuscular injection (see product literature for information on dosing).
| Likely toxicity | Ingested dose (mg/kg body weight) | Serum iron concentration at 4 hours |
|---|---|---|
Mild | <20 | 3 mg/L (55 micromol/L) |
Moderate | >20 | 3–5 mg/L (55–90 micromol/L) |
Severe | 150–300 | >5 mg/L (90 micromol/L) |
| Likely toxicity | Ingested dose (mg/kg body weight) | Serum iron concentration at 4 hours |
|---|---|---|
Mild | <20 | 3 mg/L (55 micromol/L) |
Moderate | >20 | 3–5 mg/L (55–90 micromol/L) |
Severe | 150–300 | >5 mg/L (90 micromol/L) |
Poisoning with iron is most common in children and is usually accidental.
The most common symptoms are nausea, vomiting, abdominal pain, and diarrhoea.
Stools and vomit are grey/black.
Laboratory findings include a polymorphonuclear leucocytosis and hyperglycaemia.
More severe findings include haematemesis and rectal bleeding (due to gastrointestinal corrosion), drowsiness, convulsions, and metabolic acidosis.
Treatment is supportive. Activated charcoal does not adsorb iron.
If the poisoning is severe, take blood for urgent measurement of the serum iron concentration.
Give desferrioxamine intravenously without waiting for the serum iron result. The dose is 15 mg/kg/hour. The maximum dose advised is 80 mg/kg in 24 hours.
Discuss the case with the National Poisons Information Service.
If the poisoning is mild or moderate, measure the serum iron at 4 hours. If the patient is symptomatic, consider treatment with desferrioxamine. Discuss the case with the National Poisons Information Service.
See also Desferrioxamine, p. 622 .
Blood, blood products, and anaemia: Folic acid and folinic acid BNF 9.1.2 and 8.1
Essential nutrients
Methotrexate
Trimethoprim
Co-trimoxazole
Phenytoin
Phenobarbital
Increased demand
Pregnancy
Dyserythropoiesis
Malignancy
Haemodialysis
Malabsorption
Coeliac disease
Tropical sprue
Drugs (see box)
Potential uses
Prevention and treatment of folate deficiency.
‘Rescue’ therapy to reduce bone marrow toxicity during treatment with methotrexate.
Prevention of neural tube defects during pregnancy.
Contraindications and cautions
Folic acid must be converted to folinic acid in order to act; this is inhibited by methotrexate.
Folic acid will not therefore be effective for the prevention of methotrexate-induced bone marrow toxicity during continuous administration of methotrexate; however, it is effective during intermittent administration
However, folinic acid is not used in the prevention and treatment of folate deficiency.
How to use
Whenever you suspect folic acid deficiency, find out if the patient has vitamin B12 deficiency as well. Do not give folic acid alone if there is a mixed deficiency (see later notes).
Pregnancy
The daily requirement for folic acid is usually 50 micrograms, but this rises to 200 micrograms during pregnancy.
Advise the patient to take folic acid throughout the period they are trying to conceive, and for the first 3 months of the pregnancy.
A supraphysiological dose is recommended if the woman has had a previous child with a neural tube defect or is taking certain antiepileptic drugs (phenytoin, sodium valproate, carbamazepine).
Counsel women about this; seek specialist advice in women considering pregnancy; and ensure folic acid supplementation (5 mg/day)
During treatment with methotrexate
Give folinic acid ‘rescue’ therapy on a different day from the methotrexate (usually the day after).
It is available in both oral and intravenous formulations.
Folate deficiency
The initial dose is much higher than the maintenance dose (see prescribing information).
Long-term treatment is rarely necessary; folic acid is obtained from food, so ensure that the patient has an adequate diet.
Primary prevention of ischaemic heart disease and stroke
Previous research has suggested that folic acid supplementation may reduce the risk of ischaemic heart disease and stroke. It is thought to do this by lowering the plasma homocysteine concentration. However, the most recent meta-analyses of trials have failed to show a consistent reduction in cardiovascular disease or mortality in those with a prior history of vascular disease. There is currently no convincing evidence that folic acid should be routinely used in primary prevention.
Most common and most serious adverse effects
Adverse effects are very rare; hypersensitivity is occasionally observed during intravenous infusion.
It is generally said that giving folic acid alone to a patient who is also vitamin B12 deficient can precipitate subacute combined degeneration of the spinal cord, although there is scant evidence that this is so. However, it is wise to give B12 first.
Major drug-drug interactions
The efficacy of treatment with fluorouracil (5-FU) for metastatic colorectal cancer is increased when the patient is also given folinic acid.
Monitoring
Efficacy
In suspected deficiency, measure the red cell folate or plasma folate concentration. Also measure the serum B12 concentration.
Patient information
Advise women who are considering becoming pregnant to take folic acid; this reduces the risk of fetal neural tube defects.
Prescribing information: Folic acid and folinic acid
Folic acid
Pregnancy
Previous history of a neural tube defect, 5 mg daily.
No previous history, 400 micrograms daily. This is available over the counter.
Folic acid deficiency
Initially, 10–20 mg daily.
Long-term treatment is rarely necessary.
During intermittent treatment with methotrexate for rheumatoid arthritis
Give folic acid 5 mg 3 days after each dose of methotrexate. This can reduce the haematological, gastrointestinal, and mucosal adverse effects.
Folinic acid (given as calcium folinate)
During treatment with methotrexate
Initially 15 mg every 6 hours for 24 hours
Followed by 15 mg every 6–8 hours by mouth for 2–8 doses
Usually given 24 hours after a dose of methotrexate.
Blood, blood products, and anaemia: Vitamin B12 BNF 9.1.2
Essential vitamin
Pernicious anaemia
Gastrectomy
Limited diet (vegans)
Terminal ileal disease
Blind gut loops
Bowel diverticula
Intestinal worms
Always consider whether there is also folate deficiency.
Potential uses
Treatment and prevention of vitamin B12 deficiency:
Given prophylactically after total gastrectomy (partial gastrectomy in some patients) and total ileal resection.
Contraindications and cautions
Hydroxocobalamin has largely replaced cyanocobalamin, as it has preferable kinetic properties.
If the patient has severe, undiagnosed megaloblastic anaemia, always give both vitamin B12 and folate; giving either alone can reportedly precipitate neuropathy, although the evidence supporting that is old and anecdotal.
In other circumstances, determine whether there is vitamin B12 deficiency before giving treatment.
How to use
The dose and route of administration will depend on the cause of the deficiency.
For example, if the cause is pernicious anaemia, B12 cannot be absorbed from the gut and must be given parenterally.
If the patient has established deficiency, an initial period of loading will be needed in order to replenish body stores. This is not necessary if it is given prophylactically.
Most common and most serious adverse effects
Adverse effects are rare.
Hypersensitivity to hydroxocobalamin is rare.
Major drug-drug interactions
There are no established drug interactions with vitamin B12.
Monitoring
Safety and efficacy
Measure the serum B12. Usually B12 assay is a microbiological assay, which can give false low results if the patient is taking antibiotics.
Measure a full blood count and folate (preferably red cell folate).
Patient information
Advise the patient that treatment will usually need to be lifelong.
Prescribing information: Vitamin B12
Hydroxocobalamin
By intramuscular injection.
Pernicious anaemia without neurological involvement, initially 1 mg 3 times a week for 2 weeks, and then 1 mg every 3 months.
Pernicious anaemia with neurological involvement, initially 1 mg on alternate days, until no further clinical improvement, then 1 mg every 2 months.
Prophylaxis, 1 mg every 2–3 months.
Cyanocobalamin
Available for administration by mouth for the few patients for whom this route is appropriate. Not recommended for routine use. Seek specialist advice.
Blood, blood products, and anaemia: Desferrioxamine (deferoxamine) BNF 9.1.3
Iron chelating drug
These drugs can be given by mouth for patients who cannot tolerate deferoxamine.
However, deferiprone can cause neutropenia and liver damage, and deferasirox has been associated with raised creatinine and liver function tests, so they are not used first-line.
Potential uses
Treatment of acute iron poisoning.
Chronic iron overload:
Secondary to repeated transfusions.
Haemochromatosis; note that venesection is usually preferred for this indication.
Desferrioxamine can also be used for chronic aluminium overload in renal dialysis patients.
Potential uses
Desferrioxamine is teratogenic in animals; do not give it long term to women who are pregnant. However, if it is used for acute iron poisoning, the benefit is likely to outweigh the risk.
How to use
Iron poisoning
(see also Treatment of iron poisoning box, p. 617 )
Poisoning by iron is most common in childhood and is usually accidental.
Remove iron from the stomach by lavage if the patient presents within 1 hour of the overdose.
Charcoal does not adsorb iron.
Treat with intravenous desferrioxamine according to the serum iron concentration measured 4 hours after the overdose.
Mild poisoning: <3 mg/L (<55 micromol/L); treatment not usually necessary.
Moderate poisoning: 3–5 mg/L (55–90 micromol/L); treat.
Severe poisoning: >5 mg/L (>90 micromol/L); treat.
If the dose is large (>20 mg iron/kg) or there are other signs of significant iron intoxication (e.g. acidosis, numerous radio-opaque tablets visible in the gastrointestinal tract by X-ray) treat immediately.
Chronic iron overload
Desferrioxamine is usually given subcutaneously 3–7 times per week over an 8–12-hour period (overnight).
Desferrioxamine can be given intramuscularly, but this can be painful.
Desferrioxamine can be given intravenously when the patient is receiving a blood transfusion as part of long-term treatment (e.g. in thalassaemia).
This can be via the same cannula, but do not add desferrioxamine to the blood bag or use the same line.
Give up to 2 g of desferrioxamine per unit of blood.
Most common and most serious adverse effects
Intravenous infusion can cause histamine release from mast cells; this in turn can cause hypotension, erythema, and pruritus.
Local reactions around subcutaneous infusion sites are common.
If this is a problem, add hydrocortisone 2 mg to the infusion bag.
Follow-up studies show that the changes in iron metabolism that result from long-term treatment increase the risk of infection due to Yersinia spp., Pneumocystis jirovecii, and Staphylococcus aureus.
Long-term treatment can cause lens opacities, retinopathy, and hearing disturbances.
Major drug-drug interactions
Vitamin C (100–200 mg orally) can increase the effect of desferrioxamine, but only if given separately from food.
Avoid co-prescribing prochlorperazine and levomepromazine with desferrioxamine; they can cause loss of consciousness.
Monitoring
Safety and efficacy
Long-term treatment
Measure visual acuity and perform a hearing check before long-term treatment starts and every 3 months thereafter.
Measure the serum iron and other markers of iron metabolism to tailor the dose correctly.
Patient information
Warn patients that desferrioxamine can turn the urine orange-pink to brown in colour.
Advise patients to report any changes in vision or hearing.
Prescribing information: Desferrioxamine
Acute poisoning
The usual dose is 15 mg/kg/h, given intravenously, up to a maximum of 80 mg/kg in 24 hours.
Chronic overload
In established overload the usual dose is 30–50 mg/kg daily.
Once the overload has been treated the dose should not exceed 30 mg/kg daily.
Measure the serum iron and markers of iron metabolism to tailor the dosage regimen.
Aluminium overload (specialist use)
100 mg of desferrioxamine will bind 4.1 mg of aluminium.
Minerals: Calcium salts BNF 9.5.1.1 and 9.6.4
Essential ion
Calcium is an essential component of excitation–contraction coupling in muscle cells.
Clinical features are due to the ionized calcium concentration; the laboratory measures total calcium. Most calcium is bound to albumin.
Adjust the calcium according to the plasma albumin.
Add 0.02 mmol/L to the measured calcium concentration for every 1 g the albumin is below 40 g/l.
And vice versa if the albumin is above 40 g/L.
For example, measured calcium concentration 2.25 mmol/L, albumin 35 g/L; corrected calcium concentration = 2.25 + [(40 – 35) × 0.02] = 2.35 mmol/L.
Calcium salts are included in some antacid formulations
Excessive doses can cause the milk-alkali syndrome, characterized by hypercalaemia and alkalosis
Causes
Chronic renal insufficiency (deficient vitamin D production)
Hypoparathyroidism
Vitamin D deficiency
Malabsorption
Hypomagnesaemia and hypokalaemia
Rhabdomyolysis
Clinical features
Tingling
Tetany
Mental changes
Polyuria, polydipsia
Anorexia, nausea, vomiting
Constipation
Muscle weakness
Confusion, lethargy, and depression
Late findings
Nephrolithiasis
Bone pain
Pathological fractures
Causes
Parathyroid-associated
Malignancy-associated (breast, bronchus, bone marrow, kidney)
Vitamin D-related
High bone turnover (hyperthyroidism, immobilization)
Related to renal insufficiency (severe secondary hyperparathyroidism, aluminium intoxication)
Drugs (thiazide diuretics)
Potential uses
Treatment of hypocalcaemia.
Treatment of hyperkalaemia.
Prevention of osteoporosis (with vitamin D).
Contraindications and cautions
Collection of a blood sample in a tube containing EDTA, citrate, or oxalate will give a spuriously low result.
How to use
Treatment of hypocalcaemia
Identify the underlying cause.
See later notes for an intravenous regimen if emergency treatment is required.
Treatment of hyperkalaemia
Calcium gluconate (or calcium chloride), given by intravenous injection over 3–5 minutes stabilizes cardiac membranes.
This has no effect on the serum potassium concentration.
See Potassium, p. 628 for more information.
Prevention of osteoporosis
Calcium and vitamin D supplements are recommended for patients at risk of osteoporosis over 65 years old.
See Bisphosphonates, p. 660 for more information on the treatment of osteoporosis.
Most common and most serious adverse effects
Major drug-drug interactions
Take care when giving intravenous calcium to patients taking digoxin, whose actions it will enhance.
Avoid giving intravenous calcium salts with sodium bicarbonate.
Monitoring
Safety and efficacy
Measure the serum calcium concentration and monitor clinically for hypercalcaemia.
The serum calcium concentration is not normally reduced in osteoporosis. Consider bone densitometry if this will change your treatment.
Patient information
In the prevention of osteoporosis, make sure that the patient addresses other risk factors for osteoporosis (e.g. smoking, alcohol).
Prescribing information: Calcium salts
Emergency treatment of hyperkalaemia
By intravenous injection, 10 mL of 10% calcium gluconate (or calcium chloride) over 3–5 minutes.
This has no effect on the serum potassium concentration.
Emergency treatment of hypocalcaemia
By intravenous injection, 10 mL of 10% calcium gluconate over 3–5 minutes.
Followed by a continuous infusion of 40 mL over 24 hours.
Prevention of osteoporosis (with vitamin D)
By mouth, ergocalciferol (vitamin D2) 800 IU (20 mg) and calcium gluconate 800–1500 mg daily.
Numerous oral preparations of colecalciferol (vitamin D3) and calcium are available—consult manufacturers’ instructions.
Minerals: Magnesium sulphate BNF 9.5.1.3
Essential ion
Magnesium is an essential ion that is an important co-factor in many enzyme systems. Body magnesium stores often mirror body potassium stores.
Magnesium is not well absorbed when taken by mouth.
It is commonly used as an osmotic laxative. This indication is not considered further here.
See Constipation, p. 42 for more information.
Potential uses
Treatment of hypomagnesaemia.
Treatment of some cardiac arrhythmias (e.g. torsade de pointes).
Treatment of eclampsia and pre-eclampsia.
Adjunctive role in the treatment of acute, severe asthma.
Contraindications and cautions
Avoid giving magnesium if the patient has severe hepatic insufficiency.
Magnesium can accumulate if the patient has severe renal insufficiency, but this is rare.
Excessive doses given during labour can cause neonatal respiratory depression.
How to use
Treatment of hypomagnesaemia
Body magnesium concentrations may be low when body potassium concentrations are low.
Excretion of magnesium is increased by diuretic drugs.
Potassium-sparing diuretics are also magnesium-sparing.
Patients in ICUs are often given maintenance doses of 24 mmol daily.
Treatment of arrhythmias
Intravenous magnesium is effective for certain ventricular arrhythmias, in particular torsade de pointes.
This arrhythmia can be precipitated by drugs that prolong the QT interval (see Antihistamines, p. 688 ).
Eclampsia and pre-eclampsia
Magnesium sulfate reduces the incidence of seizures in women with eclampsia.
This is a potentially fatal condition; it should be managed by an expert.
Asthma
A single dose of intravenous magnesium sulfate is an effective adjunct in the treatment of acute severe asthma.
Seek expert advice before giving magnesium.
Most common and most serious adverse effects
Adverse effects are uncommon.
Hypermagnesaemia is characterized by:
muscle weakness and reduced tendon reflexes;
nausea and flushing;
double vision and slurred speech.
Calcium gluconate can be used to treat toxicity.
Major drug-drug interactions
The combination of large doses of magnesium and calcium channel blockers in eclampsia can cause profound hypotension.
Magnesium potentiates the action of non-depolarizing muscle blockers.
Monitoring
Safety and efficacy
Measure the serum magnesium concentration and monitor clinically for hypermagnesaemia.
Patient information
This drug is usually given in an emergency.
Prescribing information: Magnesium sulphate
Arrhythmias
By intravenous infusion, 8 mmol over 10–15 minutes.
Eclampsia
By intravenous infusion, 16 mmol over 5–10 minutes, followed by 4 mmol/hour for 24 hours.
Acute severe asthma
By intravenous infusion, 1.2–2 g over 20 minutes.
Note: Magnesium sulfate 1 g is approximately equivalent to Mg2+ 4 mmol.
Minerals: Potassium chloride BNF 9.2.1.1
Essential ion
Potassium is an essential ion involved in creating and maintaining electrochemical gradients in both excitable and non-excitable tissues.
Total body potassium is about 3500 mmol, of which 90% is intracellular.
Total body potassium may be low even in the presence of a high serum concentration (e.g. in diabetic ketoacidosis).
The serum potassium concentration is tightly regulated; small changes can have important clinical effects, especially on cardiac tissues.
A raised serum potassium concentration stabilizes excitable membranes and can cause asystole.
A low serum concentration depolarizes membranes and can cause cardiac arrhythmias.
Serum potassium concentration reference range 3.5–5.0 mmol/L
Potassium chloride is the salt of choice in treating or preventing potassium depletion, since retention of potassium will not occur unless the concomitant chloride depletion is also corrected.
Potential uses
Treatment and prevention of potassium depletion from any cause (e.g. patients taking diuretic drugs or corticosteroids).
Contraindications and cautions
Do not give potassium supplements unless you know the serum potassium concentration.
Do not give supplements if the serum potassium is >5 mmol/L.
Patients with renal insufficiency are at particular risk of hyperkalaemia.
Never give undiluted potassium by intravenous injection or infusion.
Hypokalaemia can cause digoxin toxicity, even if the plasma digoxin concentration is in or even below the usual target range. Withhold digoxin and replace potassium urgently.
How to use
Patients should not normally require potassium supplements. If the serum potassium concentration is low, always consider the likely cause.
Diuretics are a common cause. Regularly review the need for these drugs and the dose. Long-term prevention of hypokalaemia is best achieved with a potassium-sparing diuretic rather than potassium supplements. Combination formulation of diuretics and potassium supplements are not recommended. See Potassium-sparing diuretics, p. 210 for more information.
Corticosteroids lower the serum potassium concentration. Remember that treatment with corticosteroids should be with the lowest effective dose for the shortest possible time.
Patients with heavy gastrointestinal loss (e.g. high-output ileostomy) may lose a lot of potassium (5–15 mmol/day). Provide supplements and consider whether losses can be reduced.
Extensive surgical (especially abdominal) procedures can result in significant potassium loss. Monitor the serum potassium closely and be prepared to give supplements.
Patients with cardiac disease are at particular risk of arrhythmias if the serum potassium concentration is low. The target concentration is usually higher in these patients.
Suggested target serum potassium concentration in patients with cardiac disease is 4–5 mmol/L
Oral potassium supplements are suitable for short-term mild potassium depletion. Review the need for supplements daily, and especially before discharge from hospital.
Enteric-coated formulations can cause intestinal ulceration and are no longer recommended.
Modified-release formulations can cause oesophageal ulceration in those with oesophageal obstruction (e.g. left atrial enlargement due to mitral stenosis); they also have a delayed onset of action. Their use is not recommended. Instead use effervescent formulations.
| Peripheral | Central | General notes |
|---|---|---|
• 40 mmol/L is the usual maximum recommended concentration that can be administered via a peripheral line • Higher concentrations (60–80 mmol/L) can be given via a large peripheral vein in severe depletion, or during strict fluid restriction • Usual maximum daily dose, 3 mmol/kg. • Usual maximum rate of infusion, 10–20 mmol/hour | • 20 mmol/100 mL is the usual recommended maximum concentration to be administered via a central line • The usual maximum daily dose is 3 mmol/kg, although this can be increased to 6 mmol/kg in severe cases • The usual maximum rate of infusion is 30 mmol/hour | • Use ready-mixed potassium infusion bags whenever possible • Adding strong potassium chloride to bags can cause layering if it is not mixed properly • The rate of replacement of potassium is limited by the rate of transfer of potassium from the extracellular to intracellular compartments • Use an infusion pump if the concentration of potassium in the intravenous fluid is above 40 mmol/L |
| Peripheral | Central | General notes |
|---|---|---|
• 40 mmol/L is the usual maximum recommended concentration that can be administered via a peripheral line • Higher concentrations (60–80 mmol/L) can be given via a large peripheral vein in severe depletion, or during strict fluid restriction • Usual maximum daily dose, 3 mmol/kg. • Usual maximum rate of infusion, 10–20 mmol/hour | • 20 mmol/100 mL is the usual recommended maximum concentration to be administered via a central line • The usual maximum daily dose is 3 mmol/kg, although this can be increased to 6 mmol/kg in severe cases • The usual maximum rate of infusion is 30 mmol/hour | • Use ready-mixed potassium infusion bags whenever possible • Adding strong potassium chloride to bags can cause layering if it is not mixed properly • The rate of replacement of potassium is limited by the rate of transfer of potassium from the extracellular to intracellular compartments • Use an infusion pump if the concentration of potassium in the intravenous fluid is above 40 mmol/L |
Most common and most serious adverse effects
Cardiac toxicity. Because the rate of replacement of potassium is limited by the rate of transfer of potassium from the extracellular to the intracellular compartment, the plasma concentration can rise rapidly (within a few hours). Follow the monitoring guidelines outlined in the next section.
Pain and phlebitis are more likely when high concentrations of potassium are given intravenously.
Extravasation causes tissue necrosis.
Oral potassium supplements commonly cause nausea and vomiting.
Major drug-drug interactions
There is a particular risk of hyperkalaemia when potassium supplements are co-prescribed with:
Potassium-sparing diuretics (e.g. amiloride, triamterene, spironolactone, eplerenone).
ACE inhibitors or angiotensin receptor antagonists; this can be severe.
Ciclosporin and tacrolimus.
NSAIDs, especially indometacin, which can worsen renal function and so cause hyperkalaemia.
Monitoring
Safety and efficacy
Measure the plasma potassium concentration before giving potassium supplements.
The continued need for oral supplements should be reviewed daily. They should not be required in the long term.
If potassium is given parenterally ( p. 629 ):
Continuous ECG monitoring is recommended if the infusion rate exceeds 20 mmol/hour.
Stop the infusion if peaking of the T waves occurs; measure the serum potassium concentration urgently.
Measure the serum potassium concentration at least daily (more often if given via a central vein).
Patients with renal insufficiency are at particular risk of hyperkalaemia.
Patient information
Advise the patient at risk of hypokalaemia to maintain a good oral intake of potassium.
The recommended dietary intake is 3.5 g (about 90 mmol) daily.
A banana contains 0.5 g and a baked potato 0.75 g of potassium.
Similarly, warn patients with renal insufficiency to avoid foods that are rich in potassium.
Explain the importance of regular measurement of serum potassium concentrations.
Prescribing information: Potassium
Oral potassium
The following are examples:
Sando K® tablets, 12 mmol potassium per tablet; usual dose 2 tablets tds.
Kay-Cee-L® liquid, 1 mmol/mL; usual dose 20 mL tds.
Parenteral potassium
Follow the guidance on dose and administration given earlier.
Withhold oral potassium supplements and any drugs that conserve potassium (see interactions section earlier in topic).
Increase gastrointestinal potassium loss. Give a polystyrene sulfonate resin (e.g. Calcium Resonium®) by mouth.
These take time to act and are only suitable if hyperkalaemia is mild and the patient is at a low risk of arrhythmias.
The patient should have continuous cardiac monitoring and resuscitation facilities should be immediately available.
Stabilize cardiac membranes with 10 mL of 10% calcium gluconate given by intravenous injection over 3–5 minutes. This has no effect on the serum potassium concentration.
Take care when giving this drug to patients taking digoxin; it potentiates the effect of digoxin and can cause arrhythmias.
Drive potassium into cells (lowering the serum potassium concentration).
Give 10 units of soluble insulin with 50 mL of glucose (to prevent hypoglycaemia) by intravenous infusion over several minutes.
Alternatives include:
Salbutamol (β2 adrenoceptor agonist), 5–10 mg by nebulized solution.
Sodium bicarbonate, 50 mL of an 8.4% solution by intravenous infusion over several minutes into a central vein.
Note, do not give through the same lumen as calcium gluconate; insoluble calcium carbonate will precipitate.
The most severe cases will require dialysis.
Most of these measures move potassium rather eliminating it; urgently investigate the cause of the hyperkalaemia.
Peaked T waves
Flat P waves
Prolonged PR interval
Widened QRS complex
Vitamins: Vitamin D analogues BNF 9.6.4 and 13.5.2
A complex group of metabolites and synthetic analogues of vitamin D
Inadequate dietary sources
Malabsorption
Repeated pregnancy
Drugs (e.g colestyramine reduces the absorption of fat-soluble vitamins)
Anticonvulsants
Potential uses
Treatment of vitamin D deficiency (usually oral colecalciferol or ergocalciferol).
Prevention of osteoporosis (with calcium).
Treatment of hypoparathyroidism (alfacalcidol).
Treatment of renal osteodystrophy (alfacalcidol).
Treatment of anticonvulsant-induced osteomalacia.
Treatment of congenital rickets.
Topical treatment of plaque psoriasis.
Contraindications and cautions
Avoid these drugs if the patient has hypercalcaemia or metastatic calcification.
Dosage reduction is not usually required in renal or hepatic insufficiency.
The hydroxylated derivatives, alfacalcidol and calcitriol, should be used if the patient has renal insufficiency.
High systemic doses of vitamin D are teratogenic in animals; therapeutic doses are unlikely to cause adverse effects.
Vitamin D enters breast milk in significant quantities.
How to use
Vitamin D deficiency
Elderly people and those who do not take vitamin D in the diet are at risk of vitamin D deficiency.
This was classically described in Asian immigrants to the UK eating unleavened bread containing large amounts of phytates, but vitamin D deficiency is now uncommon in this group.
Vitamin D and calcium supplementation reduces the incidence of osteoporosis in the elderly, even in the absence of frank deficiency.
Once the deficiency has been treated, long-term treatment is rarely necessary, unless the cause is persistent.
The most common persistent cause is malabsorption, in which very large oral doses may be required.
Prevention of osteoporosis
Hypoparathyroidism
Hypoparathyroidism can result de novo or can follow parathyroid or thyroid surgery.
Post-surgical patients should be monitored for hypoparathyroidism.
Renal osteodystrophy
Renal insufficiency leads to reduced plasma calcium and raised plasma phosphate concentrations. This stimulates parathyroid hormone (PTH) production and can lead to metastatic calcification.
The initial treatment of renal osteodystrophy is a phosphate-binding drug. Once the phosphate concentration has fallen, give alfacalcidol with calcium supplements to reduce metastatic calcification.
Anticonvulsant-induced osteomalacia
The anticonvulsants phenytoin and phenobarbital can cause osteomalacia during long-term use.
The mechanism is not fully understood, but is probably the result of enhanced metabolism of colecalciferol.
Psoriasis
The topical vitamin D analogues, calcipotriol and tacalcitol, and topical calcitriol are used for the treatment of plaque psoriasis.
They induce the differentiation of keratinocytes, reducing their proliferation.
Used topically, these drugs do not affect systemic calcium metabolism.
Most common and most serious adverse effects
The adverse effects of vitamin D analogues are related to their effects on calcium metabolism.
The most common important adverse effect is hypercalcaemia.
The symptoms of hypercalcaemia include nausea, vomiting, anorexia, thirst, and lassitude.
Alfacalcidol and calcitriol have short half-lives; this makes it easier to titrate them to the correct dose than some of the long-acting alternatives.
See Bisphosphonates, p. 660 for guidance on the treatment of hypercalcaemia.
Withdrawal of the drug or a dosage reduction may be all that is required for mild symptoms.
Vitamin D analogues used topically for psoriasis can cause local itching, erythema, dermatitis, and burning.
Major drug-drug interactions
Drug interactions are uncommon.
Thiazide diuretics reduce the excretion of vitamin D analogues; there is an increased risk of hypercalcaemia if they are given together.
Phenobarbital and phenytoin increase the metabolism of vitamin D analogues (see earlier notes). The dose of vitamin D may need to be increased.
Monitoring
Safety and efficacy
Measure the plasma calcium concentration at least weekly during the start of treatment.
If long-term treatment is required, measure the plasma calcium concentration every few months.
Measure the plasma calcium concentration if the patient has any symptoms of hypercalcaemia.
Patient information
Advise the patient to report nausea, vomiting, polyuria, polydipsia, or other symptoms that might suggest hypercalcaemia.
Advise patients using vitamin D analogues topically to wash their hands thoroughly after use.
There is evidence of diurnal variation in response to vitamin D; advise the patient to take the dose at the same time each day.
Prescribing information: Vitamin D analogues
There are many formulations of these drugs; the following are given as examples. See the earlier notes to select the most appropriate for the proposed indication.
Treatment and prevention of vitamin D deficiency and osteoporosis
Only available in combination with calcium.
Ergocalciferol 400 IU (10 micrograms) with a variable amount of calcium (depends on the formulation).
If used to prevent osteoporosis give ergocalciferol 800 IU (20 micrograms) and 800–1500 mg calcium gluconate daily.
Vitamin D deficiency due to malabsorption or chronic liver disease
Ergocalciferol by mouth, up to 40 000 units (1 mg) daily.
Hypoparathyroidism
Ergocalciferol by mouth, up to 100 000 units (2.5 mg) daily.
Renal osteodystrophy
Alfacalcidol, by mouth, initially 1 microgram daily.
Usual maintenance dose 0.25–1 microgram daily
Calcitriol by mouth, initially 250 nanograms daily.
Usual maintenance dose 500–1000 nanograms daily.
Available by injection for patients receiving haemodialysis; usual maintenance dose 500–3000 nanograms 3 times a week.
Vitamins: Vitamin K1 BNF 9.6.6
Essential fat-soluble vitamin
Phytomenadione
Lipid-soluble
Menadiol
Synthetic analogue
Water-soluble
Do not give to neonates
Potential uses
Treatment of clotting disorders that result from vitamin K deficiency.
Reduced synthesis (e.g. hepatic cirrhosis).
Drugs (e.g. warfarin and other coumarin anticoagulants); colestyramine given for primary biliary cirrhosis reduces the absorption of fat-soluble vitamins.
Nutritional deficiency.
Neonates are relatively deficient in vitamin K. This can cause haemorrhagic disease of the newborn. Vitamin K is given to prevent this. This risk is increased if the mother is taking anticonvulsant drugs.
Malabsorption of fat-soluble vitamins (A, D, E1, K) (e.g. in biliary obstruction).
Lack of enteric bacteria.
Contraindications and cautions
Vitamin K can be used to correct a clotting disorder, but is rarely sufficient on its own for treatment of haemorrhage.
Do not give menadiol (a synthetic analogue of vitamin K) to neonates; there is a risk of haemolysis.
Do not give by intramuscular injection if the patient has abnormal clotting.
Anticoagulation using warfarin or other coumarin anticoagulants will be very difficult for several weeks after a large dose of vitamin K. See case history box, p. 637 .
How to use
The Chief Medical Officer in the UK has recommended that all newborn babies should be offered vitamin K to reduce the risk of haemorrhagic disease of the newborn.
This can be given as a single intramuscular injection of 1 mg at birth; or 2 mg orally at birth, after 1 week, and after 1 month; bottle-fed babies can omit the last dose, as formula feeds contain vitamin K.
In the past some intravenous formulations of phytomenadione contained polyoxyl castor oil (Cremophor EL®), which can cause non-IgE-mediated anaphylactic (anaphylactoid) reactions when given by rapid intravenous injection. These formulations are no longer licensed in the UK but they may be available elsewhere.
Give vitamin K slowly (1 mg/min) by intravenous infusion.
If the patient has fat-soluble vitamin malabsorption give menadione, as this is water-soluble.
Vitamin K can be given to reverse anticoagulation due to warfarin and other coumarin analogues (see Warfarin, p. 124 ).
A dose of 10 mg of vitamin K will fully reverse the action of warfarin; blood clotting may not return to normal immediately, as new clotting factors will have to be synthesized.
If the patient is bleeding, see Teaching point in heparin, p. 116 for guidance.
Partial reversal of the effect of warfarin can be achieved by giving small doses of vitamin K (e.g. 0.5–2.0 mg by intravenous injection); this will require close monitoring and dose titration.
Most common and most serious adverse effects
Adverse effects are rare.
Note the advice about intravenous administration of phytomenadione.
Intramuscular injection can cause a haematoma if the patient has abnormal clotting.
Major drug-drug interactions
Vitamin K antagonizes the action of warfarin and other coumarin anticoagulants.
A 72-year-old man with atrial fibrillation and moderate mitral regurgitation had been taking warfarin for 2 years after a small stroke. He had fallen at home while doing some decorating and, having injured his chest, had been taking paracetamol 1.0 g 4 times a day for 10 days because his GP had told him that paracetamol was safe to take with warfarin. He developed a subconjunctival haemorrhage and then noticed that his urine was pink and that he was covered in bruises, although having no recollection of new injuries. He arranged to have his INR checked and was rung by the haematology laboratory that night to say that his INR was over 15. In accordance with the British Society for Haematology guidelines he was told to stop taking warfarin. Given that he had suffered a recent fall and had a lot of bruising, he was given oral vitamin K 0.5 mg in the hope of partially, but not fully, reversing the overanticoagulation. His INR was repeated the next day and was 6.2. When his INR fell below 5.0 the next day, his warfarin was restarted at a lower dose. With careful monitoring and dosage adjustment there was no further problem.
The interaction between paracetamol and warfarin is not widely appreciated. Single doses are generally safe, but prolonged therapy (1 g qds for 1 week or more) can cause marked prolongation of the INR. The guidelines for management of coumarin overanticoagulation issued by the British Committee for Standards in Haematology of the British Society for Haematology ( http://www.b-s-h.org.uk/) are given in Table 9.4 .
| INR range/presence of bleeding | Action required |
|---|---|
INR >3 and <5 (target INR 2.5) INR >4 and <5 (target INR 3.5) No bleeding | 1. Reduce dose or stop warfarin 2. Restart when INR <5 |
INR >5 and <8 No bleeding or minor bleeding | 1. Stop warfarin 2. Restart when INR <5 3. Give 1–2.5 mg oral vitamin K |
INR >8 No bleeding or minor bleeding | 1. Stop warfarin 2. Restart warfarin when INR <5 3. If other susceptibility factors for bleeding give 2.5–5 mg oral vitamin K |
Major bleeding | 1. Stop warfarin 2. Give prothrombin complex concentrate (PCC) 30 units/kg or fresh frozen plasma 15 mL/kg (if PCC not available) 3. Give vitamin K 5 mg orally or intravenously |
| INR range/presence of bleeding | Action required |
|---|---|
INR >3 and <5 (target INR 2.5) INR >4 and <5 (target INR 3.5) No bleeding | 1. Reduce dose or stop warfarin 2. Restart when INR <5 |
INR >5 and <8 No bleeding or minor bleeding | 1. Stop warfarin 2. Restart when INR <5 3. Give 1–2.5 mg oral vitamin K |
INR >8 No bleeding or minor bleeding | 1. Stop warfarin 2. Restart warfarin when INR <5 3. If other susceptibility factors for bleeding give 2.5–5 mg oral vitamin K |
Major bleeding | 1. Stop warfarin 2. Give prothrombin complex concentrate (PCC) 30 units/kg or fresh frozen plasma 15 mL/kg (if PCC not available) 3. Give vitamin K 5 mg orally or intravenously |
Monitoring
Safety and efficacy
Measure the prothrombin time (or INR—see Warfarin, p. 124 ) to assess the requirement for treatment.
Ensure that the patient is closely observed if there is a risk of bleeding.
Patient information
Discuss the recommendation that the baby be given vitamin K with women and their partners before they go into labour; record the parents’ preference in the notes.
Prescribing information: Vitamin K1
Menadiol
By mouth for prevention of vitamin K deficiency in fat malabsorption syndromes, 10 mg daily.
Phytomenadione
By mouth for prevention of haemorrhagic disease of the newborn, 2 mg at birth and on days 7 and 30.
By intramuscular injection for prevention of haemorrhagic disease of the newborn, 1 mg at birth.
By slow intravenous injection/infusion for treatment of abnormal clotting, 0.5–10 mg; see earlier notes.
