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Nobel laureate addresses pharmacy meeting



20,000 participants gathered in Anaheim, California for the 49th ASHP Midyear Clinical Meeting. Key topics included the biology of nitric oxide, Ebola virus management, medication errors with insulin and pharmacy practice issues
Christine Clark PhD FRPharmS FCPP(Hon)
Editor, HPE 
Laurence A Goldberg FRPharmS
Editorial consultant, HPE 
Research into the effects of nitric oxide has been a long and painstaking process because the molecule itself is reactive and short-lived, according to Nobel laureate, Louis Ignarro (Professor of Pharmacology, Department of Molecular and Medical Pharmacology, University of California, Los Angeles). Professor Ignarro received the Nobel Prize in Physiology or Medicine in 1998 for his discovery of the physiological role of nitric oxide. Professor Ignarro, who trained as a pharmacist before studying medicine, said that the training he received in pharmacy and chemistry served him well as a researcher.
Nitric oxide is extremely reactive by virtue of its unpaired electron. In air it rapidly oxidises to nitrous oxide. Because of its reactivity it was not considered as a naturally occurring signalling molecule. The story started with nitroglycerin – a compound that was discovered in Alfred Nobel’s dynamite factories in Stockholm – that was known to be a vasodilator. “Workers got terrible headaches and relief of angina pain”, commented Professor Ignarro. Incubation of nitroglycerin with smooth muscle results in the release of nitric oxide, which has a biological half-life of less than half a second. Experiments with nitric oxide showed that cyclic guanosine monophosphate (cGMP) levels peak before the muscle relaxation response starts. It was known that nitric oxide was a vascular smooth muscle relaxant that lowered blood pressure. It also improved blood flow and inhibited blood clotting by interfering with platelet aggregation.
However, it was not until the 1980s that the nitric oxide/cGMP system was understood. This came about through investigation of the mechanism of vasodilation caused by acetylcholine. It appeared to be mediated by a short-lived compound called endothelium-derived relaxing factor (EDRF) that eventually turned out to be nitric oxide. At this point it was realised that the chemical properties of nitric oxide made it ideal as a signalling molecule. It is highly reactive, small, lipid soluble and cannot be stored in organelles. In addition, it reacts with oxygen radicals, iron and sulphur species. All these points are advantageous because signalling molecules need to have effects that are rapidly terminated, noted Professor Ignarro. Further studies clarified the mechanism by which nitric oxide is made in mammalian cells.
Erectile function
The next development was the discovery that nitric oxide was the principal neurotransmitter mediating erectile function. In 1992, the key findings were published in the New England Journal of Medicine. A report also appeared on the front page of the New York Times and Professor Ignarro was surprised to receive a phone call from Hustler magazine. Six years later Viagra (sildenafil) (which prevents the breakdown of cGMP by inhibiting phosphodiesterase-5) was marketed.
Nitric oxide plays a critical role in cardiovascular function, said Professor Ignarro. It is produced in the vascular endothelial cells and is responsible for numerous physiological actions including adjusting vascular tone and blood pressure, prevention of platelet adhesion and anti-inflammatory effects. Nitric oxide deficiency is associated with metabolic syndrome, he added. In fact, nitric oxide is essential for good health – a healthy diet and aerobic exercise increase nitric oxide formation, whereas a diet high in fat and salt and a sedentary life style decreases nitric oxide formation. Pomegranate juice and salmon are particularly good for increasing nitric oxide formation, he noted.
In conclusion, Professor Ignarro said that future drug developments based on nitric oxide could include products for memory disorders, irritable bowel, bladder incontinence and glaucoma. There could also be topical products for tanning and skin whitening because ultraviolet light stimulates nitric oxide formation and melanogenesis, he added.
Errors with insulin
Transmission of viral hepatitis is just one of the problems that has been reported with the use of insulin pens in hospitals, explained Michael Cohen (President, Institute for Safe Medication Practices (ISMP), Pennsylvania, USA). Insulin pens are convenient to use on hospital wards because they are labelled with the product name and strength and it takes less time to prepare and administer a dose than with insulin vials and syringes. However, there are reports of hospitals using pens for multiple patients and putting them at risk of blood-borne infections. The problem arises (even when needles are changed) because pens sometimes allow retrograde flow of small amounts of blood into the insulin reservoir. Even when pens are used for single patients, incidents in which patients receive insulin doses from another patient’s pen, are “alarmingly frequent”, said Dr Cohen.
In response to published events, one hospital developed a system using barcodes that linked a specific insulin pen to a designated patient.
Furthermore, the system could identify situations where the nurse received a ‘wrong pen’ alert but manually overrode the system and administered the injection. In the first month of operation no fewer than three ‘wrong pen’ incidents were recorded. In the first, the nurse withdrew the dose from the pen cartridge using an insulin syringe. In the second, the nurse had two pens in her pocket and inadvertently used the wrong one. Unfortunately the pen used belonged to a patient with active hepatitis C. In the third incident, the nurse found two pens in the patient’s medication supplies, both with the correct location. The nurse did not notice that one had been dispensed for the previous patient but had not been removed after the patient was discharged. None of these incidents occurred because the nurse though it was acceptable to use another patient’s pen – in each case the nurse thought she had the correct pen, Dr Cohen emphasised.
Other problems with insulin pens included over- and under-dosing due to misunderstandings about how the pens work. The ISMP has set up an Insulin Safety Center for Consumers (see Resources) on its website to help to reduce errors with insulin, said Dr Cohen.
Sliding-scale insulin
Insulin management in the hospital setting is complex and the use of insulin without routine glycaemic protocols is unsafe, according to Susan Cornell, (Associate Professor of Pharmacy Practice, Midwestern University, Chicago College of Pharmacy, USA). Insulin is the correct drug to use in the inpatient setting because it is more flexible and more effective than oral hypoglycaemic agents. Critically ill patients require intravenous insulin but others can be managed with subcutaneous insulin, she continued. The most physiological way to administer insulin is to “think like a pancreas” and mimic the blood insulin profile that it would naturally produce, she said. In practice, this means administering a basal (long-acting) insulin to provide a low background level and then giving boluses of short-acting insulin at mealtimes. Regular blood glucose measurements and ‘corrective’ doses (of short-acting insulin), adjusted for the individual’s insulin sensitivity, may also be required. In this way an accurate picture of insulin requirements can be established. The danger of sliding-scale insulin administration, which uses a ‘one size fits all’ approach, is that it is reactive, does not meet physiological needs and is associated with more hypoglycaemic events. “Better control can be achieved with basal-bolus insulin dosing”, said Dr Cornell.
Turning to concentrated insulin products, Dr Cornell commented that they are necessary for people with insulin resistance who require large doses but have no place in routine management of patients with ‘normal ‘requirements. The normal physiological insulin output never exceeds 50 units per day, she noted.
Nearly 49,000 pairs of gloves and 12,000 sets of scrubs were used in the care of three patients with Ebola virus disease (EBV), Andrew Faust (Critical Care Pharmacy Specialist, Texas Health Presbyterian Hospital, Dallas, USA) told the audience in a session devoted to the management of EBV. Dr Faust’s hospital – the first in the US to diagnose EBV – is not an academic centre and had no biocontainment facilities before this episode. A 52-year old female missionary returned to the USA after working in Sierra Leone for six weeks. She developed fever, malaise and diarrhoea that could not be controlled with OTC medication and after three days she drove herself to the emergency room.
Formerly known as Ebola haemorrhagic fever, haemorrhage is actually a late-stage phenomenon. The incubation period is about ten days but can be as long as 21 days. There is presumed to be a zoonotic reservoir for the disease, possibly bats, said Dr Faust. In the current outbreak, which started in March 2014, the case fatality rate is about 35%. By December 2014, 30-40 patients had been treated outside West Africa. Early stage disease is associated with fever, malaise, nausea and vomiting with leucopenia, thrombocytopenia and raised transaminases. This is followed after five days by an acute phase, in which there can be severe gastro-intestinal symptoms with a daily output of eight to ten litres of diarrhoea accompanied by hypotension, coagulopathies, electrolyte disturbances and renal failure. The late phase can include immunosuppression, rapid deterioration, anuria, respiratory failure and haemorrhage.
Management of patients with EBV involves infection control measures, supportive care and, possibly, the use of investigational drugs. Dr Faust recommended contacting local (State) health department and the Centres for Disease Control for further advice. The patient should be isolated immediately. “Nothing that goes into the room should come out until the patient is definitely negative for EBV”, said Dr Faust.
Electrolyte management is critical because of the vast fluid losses. This involves close monitoring of the patient’s electrolyte status, which can be a problem because of the risks of blood-borne infection for laboratory staff. The laboratory should be forewarned and the laboratory director should be a member of the core clinical team. Standardised collection and run times are advisable because it is necessary to decontaminate the instruments afterwards. Point-of-care analytical devices, ideally wireless, should be used whenever possible, said Dr Faust. Fluid resuscitation is essential to combat the massive fluid losses and unrelenting high fever.
Gastrointestinal output should be matched with crystalloids. They may need to be combined with colloids if there is an element of liver failure. Other treatments can include antibiotics if bacterial superinfection occurs and paracetamol for fever, especially during the first week. Anti-diarrhoeal agents can also be helpful. EBV is not an enteric infection, unlike Clostridium difficile infection where anti-motility agents can be detrimental, noted Dr Faust. In this case, the patient was given Lomotil (diphenoxylate and atropine).
Describing the clinical pharmacy input, Dr Faust recommended that a “point person” be identified to attend all meetings and coordinate pharmaceutical care. “This is an eight-day-per-week” job with numerous meetings”, he said. The pharmacist should attend daily rounds but it is not necessary for the pharmacist to enter the patient’s room. The greatest danger to staff occurs in the doffing of personal protective equipment and so the fewer staff involved the better.
Describing the logistics of caring for EBV patients, Patricia Kuban (Director of Pharmacy, Emory Hospital, Atlanta, Georgia, USA) emphasised that the multidisciplinary Ebola team includes many non-clinical staff such as facilities management and media relations personnel. It is also necessary to contact water authorities and waste disposal agents, she added. Communications within the hospital are also critical. At Emory Hospital many staff were unware that the hospital had a serious communicable diseases unit (SCDU) and much effort was put into educating and training staff to allay fears about the disease and emphasise the robustness of the hospital’s EBV planning process. Another important aspect of EBV care is to respect and protect the privacy of patients with ABV – regardless of media interest, said Ms Kuban.
Ideally the pharmacy should ensure that the SCDU is fully stocked with intravenous fluids before a patient arrives. A dedicated SCDU emergency cart is also held outside the ante-room. Any drug that is taken into the patient room does not come out, even if it is not administered; it is treated as waste, explained Ms Kuban. All waste from the patient room is autoclaved and then sent for incineration.
Speakers commented that public fear of EBV is such that some waste companies have declined to handle the ash from incinerated EBV waste.
Pharmacy practice – lessons learned
Current health care costs are unsustainable and two key questions that pharmacy managers need to ask are, “Are we a good business?” and, “Should we outsource the work if we are not very good?”, according to Marianne Ivey (Professor of Pharmacy Practice and Administrative Sciences, University of Cincinatti, Ohio, USA). Pharmacy services need to provide more quality care with less expensive labour by using technicians and technology. It might also be possible to create revenue streams using pharmacy expertise. In short, pharmacy services have to become efficient or buy from outside, she continued.
In the USA, there is now a heavy emphasis on ambulatory care with goal of keeping patients well and thereby decreasing costs. Pharmacists have a role in here in educating patients and improving adherence, she said. Young pharmacists would be well advised to seek training in areas such as paediatrics and oncology with a view to delivery ambulatory services in these specialties.
Dr Ivey concluded that inter-professional education and practice will support improved delivery of effective care. However, pharmaceutical sciences will remain an important foundation for pharmacy practice.
ISMP Insulin Safety Center for Consumers. 
A resource dedicated to medication error prevention with the use of insulin.
The 49th American Society of Healthsystem Pharmacists Midyear Clinical Meeting took place on 7–11 December 2014 in Anaheim, California, USA.

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