Drugs exert their therapeutic and toxic effects by acting on cells within the body. When a drug interacts with a cellular receptor, it initiates the chain of biochemical events leading to a drug’s effects.
• An agonist is any substance that switches a receptor on and initiates cellular activity
• A substance that turns off a receptor is an antagonist or blocker.
The kidneys play a large role in the elimination of many drugs from the body, and as kidney function declines, the amount of drug excreted can reduce dramatically. In addition, the way drugs are handled within the body can be markedly affected, which is also affected by dialysis.
• Patients with renal impairment (includes both CKD and AKI) can therefore require different doses of certain medications compared with the general population
• How the drug is absorbed, distributed, metabolized, and excreted can all be affected in renal impairment and dialysis, so each of these factors need to be taken into consideration
• An accurate assessment of kidney function is required prior to making a decision about drug dosage.
Drug absorption may be affected in renal impairment. The doses of drugs are not routinely altered to take absorption into account, but if quick onset is required, the dose or route of administration may need to be changed.
Drug distribution varies and drugs may:
• Remain free (unbound) in the plasma
• Bind onto plasma proteins, e.g.:
• Alb: ↓ serum Alb 1° ↑ free drug and ↑ side effects, particularly a problem if a drug is >80% protein bound, e.g. phenytoin or warfarin
• uraemia: ↓ drug binding of drugs to plasma proteins → ↑ free drug which may cause toxicity
• care must be taken when interpreting drug blood levels to take account of the ↑ in free drug, which can cause toxicity since total (bound + free) drug concentrations are often reported and not active free drug levels
• Bind on to other tissues:
• Absorbed into fat deposits around the body.
Effects of extracellular fluid volume
Marked oedema or dehydration may affect levels of certain drugs.
• The excess fluid present in oedema will tend to dilute drugs
• In dehydration, drugs will become more concentrated
• In practice this only affects drugs with a small volume of distribution (vd <50L), e.g. gentamicin.
Many drugs are metabolized in the liver by a series of enzymes, for example, the cytochrome P450 monooxygenase system, and this process is generally unchanged in CKD. The kidneys metabolize a few drugs and this may be slower in CKD leading to increased drug levels and toxicity. Consideration should be given to vitamin D supplementation (see p. [link]) or insulin requirements.
• The kidney converts 25-hydroxycholecalciferol to the active form of vitamin D 1α,25-dihydroxycholecalciferol:
• vitamin D supplementation—either the active drug (calcitriol) or a preparation requiring metabolism by the liver, i.e. 1α-hydroxycholecalciferol (alfacalcidol).
The kidneys are responsible for the elimination of many drugs and their metabolites. As kidney function declines the amount of drug or metabolite that is eliminated is reduced and will accumulate in the body, possibly causing side effects. With some drugs, it is the pharmacologically active metabolite which accumulates and causes side effects, e.g. pethidine → norpethidine causing CNS stimulation or seizures.
When deciding on drug dosage it is important to take into consideration that most drug companies use CrCl and not eGFR for advice on drug doses. For most drugs there is guidance giving a range of doses according to the level of kidney function.
Ideally, drugs with the following characteristics should be used in patients with renal impairment:
• Large therapeutic index
• Low adverse effect profile
• Not highly protein bound
• Unaffected by fluid balance
• No renal excretion of active drug or metabolites
• Action unaffected by altered tissue sensitivity
• Can be given in a small volume if given IV.
Once a drug has been chosen that meets as many of these criteria as possible, guidance on dosing should be sought from the drug’s summary of product characteristics and from one of the widely available renal drug dosing reference sources.1,2
• If loading dose required, may be lower in CKD
• Maintenance doses and the dosing frequency will depend on the level of kidney function
• The alterations required tend to be drug specific, depending on the therapeutic effect desired, and the toxicity profile of that drug.
Drugs removed during dialysis
Some drugs are removed from the body during dialysis.
• If a drug is removed by dialysis, the drug should be given post dialysis
• If the drug is to be given during dialysis, the dose should be administered as close to the end of dialysis as possible or during washback
• The type of dialysis used will also affect how much drug is removed:
• vancomycin is removed by HDF and high-flux HD, but not by low-flux HD or CAPD
• metronidazole is not removed by CAPD but is removed by low-flux and high-flux HD and HDF
Some drugs can be administered IP, e.g. antibiotics to treat peritonitis, or heparin to prevent or reduce fibrin. Information on giving drugs in this way can be found in the Renal Drug Handbook.1
Doses of drugs may vary according to local protocols.
Dose alterations and caution
Drugs with the following features require caution in renal impairment:
• Excreted by the kidney
• A narrow therapeutic index
• with reduced kidney function, the use of drugs which are nephrotoxic should be avoided if at all possible
• using a nephrotoxic drug in an anuric patient with ESKD receiving dialysis, will not cause any further damage to the kidneys
• need to be aware of other side effects e.g. gentamicin is nephrotoxic but is also ototoxic. Incorrect dosing in a patient with no kidney function can still lead to irreversible loss of hearing and vestibular damage
• Possess toxic side effects.
Drug-induced kidney damage can be caused by:
• ATN: aminoglycosides, NSAIDs, ciclosporin, digoxin, phenytoin, quinolones
• Interstitial nephritis: allopurinol, azathioprine, ACEIs, vancomycin
• Crystaluria: methotrexate, aciclovir
• GN: ACEIs, NSAIDs, penicillin.
Drugs that require monitoring
ACEI and ARB
• Avoid NSAIDs if at all possible
• Particularly avoid in combination with ACEI because of the ↑ risk of nephrotoxicity and hyperkalaemia:
• check kidney function 48–72hrs after starting and discontinue therapy if ↑ serum Cr >30%, or ↓ eGFR >25%
• NSAIDs should be used with caution in uraemic patients who are predisposed to GI bleeding.
• Avoid compound analgesics
• Weak opioids (e.g. tramadol or dihydrocodeine), observe for side effects and notify medical staff
• Stronger opiates, e.g. hydromorphone or oxycodone —commence on low dose and titrate as they have a prolonged half-life. Observe for any adverse effects, e.g. nausea, vomiting, constipation, itching, sweating, dry mouth, drowsiness, hallucinations, respiratory depression, myoclonus, and notify medical staff.
With antibiotic therapy, a high dose is generally required to achieve effective bactericidal blood levels but, at the same time, it is important to avoid potentially toxic side effects. It is necessary to be aware of those antibiotics that are excreted via the kidneys and likely to have toxic side effects.
• Amoxicillin is excreted via the kidneys, but is generally used in normal doses because it is not particularly toxic. However, ceftazidime can readily cause seizures, so the dose interval must be ↑ from 8hrs to 24hrs to avoid accumulation and toxicity
Awareness of polypharmacy
Patients with renal impairment often take many drugs, e.g. 2–3 of anti-hypertensives, diuretics, phosphate binders, aspirin, PPI, statins, iron tablets. It is important to be aware of potential drug interactions.
• E.g. phosphate binders will tend to bind to iron tablets in the gut and prevent the iron from being absorbed into the body. They should be taken at least 1hr apart
• Alternatively, a patient may be stable on a given drug regimen, and then another drug is added which may affect the drugs they are already taking:
• e.g. kidney Tx recipient who is already taking IS drugs ciclosporin, azathioprine, and prednisolone, then develops gout and is prescribed allopurinol There is an interaction between allopurinol and azathioprine → large ↑ in blood levels of azathioprine which can cause severe bone marrow suppression.
A generic medicine contains the same active ingredient and has the equivalent efficacy of the original brand which no longer holds the patent. These medicines still undergo all of the safety and quality requirements as the original product. These drugs may be substantially cheaper to purchase than the original.
• For the majority of drugs, the generic version produces exactly the same clinical effect, and is ∴ fully interchangeable with the original, e.g. antihypertensives, prednisolone, azathioprine, mycophenolate mofetil
• For some drugs, where there is a narrow therapeutic range, the generic drugs are not interchangeable, e.g. ciclosporin, tacrolimus, epileptic medicines.
Those drugs that are not interchangeable should be prescribed by brand.
Biosimilar medicinal products
Biosimilars are biological products which are similar, but not exactly the same as the original product on the market, e.g. subsequent versions of erythropoietin, growth hormone, that are made by a different company.
▶Not necessarily interchangeable as may have different therapeutic effect.
There are many herbal remedies available which are not subject to the same vigorous testing as pharmaceuticals. Some of these have been proven to be harmful to the kidney and some interact with other medications patients may be taking. When looking at the drugs that patients are taking, they should be asked if they take any OTC products or herbal remedies. There are numerous herbal remedies which have adverse effects for those with CKD. For example:
• Aristolochia is commonly used in Chinese herbal remedy and has been proven to cause irreversible damage to kidneys
• St John’s wort is a herbal remedy for depression that can interact with medications, reducing their efficacy, e.g. simvastatin, ciclosporin.
The UK Medicines Health products Regulatory Authority (MHRA) have developed a certification process with the aim of regulating herbal remedies. If a traditional herbal remedy (THR) carries a MHRA certification mark, it indicates the herbal medicine has been registered and met with the required safety and quality standards (however, the remedy may still be nephrotoxic or interact with other medications).4
Patients should be advised not to take any herbal remedy unless they have discussed it with their pharmacist or doctor. There are some useful websites which have information on many herbal medicines, however they do not cover all those available.5–7
• Avoid nephrotoxic drugs in CKD and AKI:
• if these drugs are necessary, keep the course as short as possible
• monitor kidney function closely.
• Choose a drug with the characteristics listed on p. [link] if possible
• Assess the degree of renal impairment and adjust the dose accordingly; refer to the Renal Drug Handbook1
• ▶ the drug companies’ information is based on renal function calculated using Cockcroft and Gault formula rather than MDRD
• For a patient on RRT, time administration of the drug after dialysis, depending on the type of dialysis and the extent to which the drug is removed
• For the majority of drugs, the general principle is to start with a low dose and ↑ slowly to obtain the desired response whilst monitoring the patient for side effects
• Avoid drugs that interact with drugs that the patient is already taking
• For drugs with a narrow therapeutic range, take blood levels after an appropriate time and interpret the levels carefully to ensure that dose adjustments are made correctly
• The prescriber should use the simplest regimen possible
• Keep the number of drugs prescribed to a minimum
• Use once-daily dosing wherever feasible to aid adherence.
In 2005, a report from the National Co-ordinating Centre for NHS delivery and organization of research and development (R&D) suggested that between a third and half of medicines prescribed are not taken as intended for long-term conditions.3 This has both an effect on the patient’s health and well-being and the healthcare provider’s costs (see pp. [link]–[link] for adherence issues). This can be for a variety of reasons and can be intentional or unintentional.
Interventions to promote medication adherence
• Patient-centred care:
• individualized approach and involve the patient in decisions about their medication to the level they prefer, provide the aims, side effects, risks and benefits of the medicine
• assess the patient’s ability to make decisions regarding their health, e.g. cognitive impairment, mental health problems
• effective communications skills supported by educational materials at a level appropriate for the patient. Involve the family/carer where the patient agrees, to enable them to be involved in the decision-making process and support management and administration if required
• non-judgemental approach and accept that some patients will not accept advice on taking a medicine
• review the patient’s knowledge, understanding, and concerns on their medicines regularly
• provide positive feedback and encouragement to those who are adherent
• Assessing adherence:
• ask questions about their medicines using a non-blame approach and provide an explanation of why you are asking, e.g. have they missed any doses in the last week?
• review repeat prescription record liaising with the pharmacy to identify those patients who require additional support
• Interventions to increase adherence:
• discuss with the patient the reason/s for not taking their medicines, e.g. concerns about side effect, health beliefs (intentional non-adherence), or impracticalities of taking the medicine (unintentional adherence)
• individualize interventions, e.g. discuss their concerns, offer appropriate support and education, minimize complexity if possible, use of multicompartmental systems, adjust dose or drug where possible if causing unwanted side effects, alter timing of medicines, diary to monitor taking their medicines
• Good communication between healthcare professionals regarding patients medicines, e.g. transfer between health services.
Non-medical prescribing refers to specially trained nurses, optometrists, pharmacists, physiotherapists, podiatrists, and radiographers who work within their competence as either an independent or supplementary prescriber.
Three types of non-medical prescriber
• Autonomous, prescribes independently from the British National Formulary (BNF)
• Other than medical personnel, only nurses, pharmacists, and optometrists can currently train to become independent prescribers:
• may prescribe any licensed medicine; however, it must be within their training and clinical competence
• restrictions include prescribing some controlled drugs and blood products
• may prescribe blood clotting factors, albumin, and antibodies as they are considered to be medicinal products
• Nurse prescribers may give directions for the administration of drugs for a condition which is within his/her competence:
• the provision is that the nurse is satisfied that the person they are giving the instructions to is competent to administer the prescribed medicine.
Community practitioner nurse prescriber (CPNP)
E.g. district nurse, health visitor, or school nurse.
• Independently prescribe from a limited formulary called the Nurse Prescribers’ Formulary for Community Practitioners found in the BNF.
• Involves the prescribing of medicines in line with a clinical management plan which has been agreed between the supplementary prescriber, doctor and patient
• Medicines can be given by another professional with the instructions of an independent prescriber or via a local arrangement.
Benefits of non-medical prescribing
• Utilize the skills and expertise of a group of professionals
• To improve patient access to medicines, advice, and treatment across the NHS
• Enhance patient care; improve patient choice without compromising patient safety
• Provide a flexible service for patients
• To contribute to more flexible team working across the NHS
• Nurses working with CKD patients have autonomy to manage patients more efficiently and in a timely manner.
Beckwith S, Franklin P. Oxford Handbook of Nurse Prescribing. Oxford: Oxford University Press; 2007.Find this resource:
1. Ashley C, Currie A. Renal Drug Handbook, 3rd edn. Oxford: Radcliffe Medical Press; 2009. Available at: <http://xa.yimg.com/kq/groups/16749867/1032282199/name/Renal+Drug+Handbook.pdf> (accessed 29 April 2012).Find this resource:
2. Bennet WM, Aronoff GR, Berns JS, et al. Drug Prescribing in Renal Failure, 5th edn. Philadelphia, PA: American College of Physicians; 2007.Find this resource:
3. NICE. Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. Clinical guideline CG79. London: NICE; 2009. Available at: <http://www.nice.org.uk>Find this resource:
4. MHRA. Herbal medicine advice for consumers. London: MHRA; 2012. Available at: <http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Herbalmedicines/index.htm> (accessed 29 April 2012).Find this resource:
5. British Herbal Medicine Association. Available at: <http://www.bhma.info/resources/links.html> (accessed 6 May 2012).
6. National Kidney Foundation. Use of herbal supplements in chronic kidney disease. Available at <http://www.kidney.org/atoz/content/herbalsupp.cfm> (accessed 6 May 2012).
7. Patient.co.uk. Alternative/complementary therapy, 2012. Available at: <http://www.patient.co.uk/showdoc/6/> (accessed 26 April 2012).
British National Formulary. Available at: <http://www.bnf.org>
Department of Health. Non-medical prescribing programme. Available at: <http://www.dh.gov.uk/en/Healthcare/Medicinespharmacyandindustry/Prescriptions/TheNon-MedicalPrescribingProgramme/index.htm>
National Prescribing Centre. Non-medical prescribing. Available at: <http://www.npc.nhs.uk/non_medical/>
Nursing and Midwifery Council (NMC). Medicines and prescribing. Available at: <http://www.nmc-uk.org/Nurses-and-midwives/Prescribing>