October 2015
“Click” clinical initiatives, research and current updates in treatment
Review of Inhaled Medications for COPD Chris Henry, Epic Pharmacy Northside Chronic obstructive pulmonary disease (COPD) is very common in Australia and a major cause of disability, hospital admission and premature death.1 COPD is an umbrella term that includes emphysema, chronic bronchitis and chronic asthma.1 Asthma and COPD share a number of common traits and some patients will suffer from a combination of these conditions. The key distinguishing factor between these conditions is that airway dysfunction is mainly reversible in asthma; this is not the case with COPD.12 COPD cannot be cured or reversed, but rather the goal is optimal management. The Australian and New Zealand guidelines (known as “The COPD-X Plan”) summarise current evidence around optimal management of people with COPD. The guidelines state that when treating COPD, prescribers should:1 Confirm the diagnosis and assess severity Optimise function Prevent deterioration Develop a support network and encourage self-management Manage eXacerbations Optimal management of COPD follows a stepwise approach, guided by symptom severity.2
The introduction of new inhaled drugs and devices in recent years has the potential to cause confusion among consumers and healthcare providers. Up to 90% of patients use incorrect inhaler technique, resulting in inadequate drug deposition with the potential for increased exacerbations and unnecessary escalation of therapy.3 Inhaler technique should be reviewed as often as possible and the healthcare provider’s ability to demonstrate correct operation of any inhaler device is vital to ensure optimal therapeutic outcomes. There are currently in excess of 25 distinct inhalers available in Australia (Table 1), all of which can be divided into the following categories.
Pressurised Metered Dose Inhalers (pMDI) These “older generation” devices deliver medication in the form of an aerosol. The drug is mixed with a propellant in a metal canister and must be shaken before each use. The canister, housed in a plastic holder with mouth piece is depressed whilst the patient inhales in order to deliver the dose. Optimal technique with this device requires dexterity, hand strength and coordination.7 For individuals who struggle to coordinate inhalation and actuation, the pMDI can be used with a volumatic spacer. Alternatively, some drugs are also available in ‘breath-actuated’ inhalers which do
not require the same hand strength to press the canister, or the coordination to concurrently inhale.
Dry Powder Inhalers These devices deliver medication into the lungs in the form of a powder which can be either preloaded into a disposable device or provided in a capsule with a separate reusable device. The specific technique varies between each device in this class – consult the National Asthma Council4 and NPS MedicineWise5 websites for detailed instructions. However, some key points are consistent throughout these devices; do not exhale into the device or submerge when washing (the powder may cake when exposed to moisture); regularly check the dose counter and expiry, only clean the device with a tissue or dry cloth. Prescribers should consider the patient’s inspiratory flow strength before choosing one of these devices as they may not be a practical option for acutely unwell or frail patients.6 As with inhaler devices, there are an ever increasing number of inhaled drugs available to manage respiratory conditions. Fortunately, the newly approved drugs are essentially variations of existing drugs and can be summarised in the following three categories. For further details and resources see the Lung Foundation Australia website.13
Short-acting Bronchodilators
Long-acting Bronchodilators
Inhaled Corticosteroids (ICS)
Short-acting beta2-agonists (SABAs) and short-acting muscarinc antagonists (SAMAs) are used as first line therapy in patients with COPD. SABAs work by relaxing bronchial smooth muscle and have a rapid onset (5-15 minutes) and a short duration of action (3-6 hours).8 SAMAs promote bronchodilation by inhibiting cholinergic bronchomotor tone and have a very similar onset (3-5 minutes) and duration (up to 6 hours) of action to SABAs.9 These medications are referred to as ‘relievers’ and can be used as often as necessary to relieve acute dyspnoea.8 At high doses, SABAs commonly cause tremor, palpitations and headache while SAMAs are likely to cause dry mouth, throat irritation and dizziness.8 Patients should ensure correct storage and easy access of their reliever device.
Long-acting beta2-agonists (LABAs) and long-acting muscarinc antagonists (LAMAs) are indicated for patients who remain symptomatic despite optimal use of short-acting agents at therapeutic doses. LABAs exert bronchodilation via the same mechanism as SABAs however time to onset is longer (within 30 minutes),8 as is duration of action (12 to 24 hours).8,10 LAMAs exert bronchodilation via the same mechanism as SAMAs and the effect typically lasts greater than 24 hours except for aclidinium which is more rapidly metabolised and requires twice daily dosing.11 Adverse effects of these agents are the same as for their short-acting counterparts. Patients should be encouraged to use their short-acting bronchodilator before their long-acting inhaler to reduce airway resistance and increase drug deposition.
These agents are indicated as an addition to maintenance long-acting bronchodilator therapy for patients with two or more exacerbations per year. These drugs reduce airway inflammation and bronchial hyperreactivity.8 As with the long-acting bronchodilators, these drugs do not exert their effect rapidly enough to be used as relievers and must be used regularly to prevent exacerbations. When using ICS, patients must always be encouraged to rinse their mouth out with water after each use. Deposition of the steroid onto the oral mucosa can cause impairment of the local immune system and increase the risk of opportunistic infection, predominantly oropharyngeal candidiasis.8
aclidinium & eformoterol
LABA + LAMA
Bretaris®
aclidinium
LAMA
Incruse®
umeclidinium
Ellipta®
LAMA
Anoro®
umeclidinium & vilanterol
LABA + LAMA
Breo®
fluticasone furoate & vilanterol
ICS + LABA
Bricanyl®
terbutaline
SABA
Turbuhaler®
Oxis®
eformoterol
LABA
Pulmicort®
budesonide
ICS
Symbicort®
budesonide & eformoterol
ICS + LABA
Accuhaler®
Serevent®
salmeterol
LABA
Flixotide®
fluticasone propionate
ICS
Seretide®
fluticasone propionate & salmeterol
ICS + LABA
Table 2: Guide to incompatible (duplicated) inhaler types (modified from Lung Foundation Australia1).
Dry powder capsules (loaded into device) HandiHaler®
Spiriva®
tiotropium
LAMA
SABA
Aerolizer®
Foradile®
eformoterol
LABA
SAMA
Seebri®
glycopyrronium
LAMA
LAMA
Onbrez®
indacaterol
LABA
LABA
Ultibro®
indacaterol & glycopyrronium
LABA + LAMA
Ventolin®
salbutamol
SABA
Atrovent®
ipratropium
SAMA
Ventolin®, Asmol®
salbutamol
SABA
Flixotide®
fluticasone propionate
ICS
Qvar®
beclomethasone
ICS
Alvesco®
ciclesonide
ICS
Seretide®
fluticasone propionate & salmeterol
ICS + LABA
Flutiform®
fluticasone propionate & eformoterol
ICS + LABA
Spiriva®
tiotropium
LAMA
Spiolto®
tiotopium & olodaterol
LABA + LAMA
Symbicort®
budesonide & eformoterol
ICS + LABA
Airomir®
salbutamol
SABA
Qvar®
beclomethasone
ICS
Breezhaler® Rotahaler®
Respimat® Rapihaler®
Breath-actuated metered dose inhaler Autohaler®
LABA + LAMA ICS + LABA
Pressurised metered dose inhaler
“Inhaler”
LABA + LAMA
Brimica®
ICS + LABA
Genuair®
ICS
Clinical Effect
LAMA
Active ingredient(s)
LABA
Brand
Dry power inhalers
SAMA
Device
SABA
Table 1: Currently available inhalers, categorised by type (compiled from AMH2015 and pbs.gov.au).
Fixed-dose combination (FDC) devices combine drugs from two classes (i.e. LAMA+LABA or ICS + LABA) and are designed to simplify the patient’s drug regimen. Best practice dictates that the prescriber trial each individual agent before a FDC inhaler is prescribed. Healthcare providers should be particularly vigilant of unnecessary duplication of therapy, particularly when a new inhaler is prescribed (Table 2).
(Newly approved inhalers in italics above – awaiting PBS approval at time of writing.)
Inhaled medications pharmacotherapy has become increasingly dynamic in recent years. In order to remain up to date and optimise their patients’ outcomes, practitioners should utilise health professional resources such as those available online through Lung Foundation Australia13, NPS Medicinewise14, manufacturers websites (particularly for the newer inhalers), or ask your Pharmacist to assist. References available on request.
What’s new G6PD – The Key to Red Blood Cell Survival Liz Chamberlain, Anne-Marie Sweett, Epic Pharmacy Murdoch Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common causes of serious adverse drug reactions. It was discovered in 1956 when an increased incidence of haemolytic anaemia was observed in patients prescribed the antimalarial drug primaquine. A low activity of G6PD was noted in these patients and it was therefore postulated that G6PD was critical for the survival of these red blood cells.1 G6PD is an enzyme that catalyses part of the pentose monophosphate shunt, which is a biochemical pathway responsible for energy production via glycolysis (it is also responsible for the production of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH)). NADPH maintains a molecule called glutathione in its reduced state, the role of which is to protect cells from oxidative stresses induced by illness, metabolic abnormalities like ketoacidosis, drugs like primaquine, chemicals like henna and foods like fava beans. Unlike other cells in the human body, red blood cells do not contain mitochondria and therefore depend on this pentose monophosphate pathway for the production of NADPH. In its absence the red cells may not be able to withstand the oxidative stresses and therefore rupture and die.1 Since being discovered, G6PD deficiency is now acknowledged as the most common enzyme deficiency disorder in the world, affecting 400
million people worldwide.1,3 It is a hereditary genetic defect disorder caused by mutations in the G6PD gene commonly seen in people of African, Mediterranean or Asian descent.3 Like haemophilia and colour blindness, males are primarily affected and females tend to be carriers. The severity of the disease is dependent on the extent of the genetic mutation, but does not usually affect life expectancy, nor reduce the quality of life. Patients with minimal G6PD deficiency are less likely to experience haemolysis than those with a greater deficiency.1 The World Health Organisation (WHO) have classified G6PD deficiency according to the degree of deficiency and the severity of haemolysis. Class I individuals (those with less than 10% of normal G6PD activity) are rare but have a severe disease that is likely to manifest with chronic haemolytic anaemia even in the absence of drugs, chemicals or infection. Class II have a severe deficiency and are likely to present with intermittent haemolysis triggered by drugs, chemicals or infections and Class III have a moderate deficiency (10-60% of normal) and present with intermittent haemolysis associated with drugs, chemicals and infection. Patients with class IV or V are thought to have no significant clinical issues.4 Since the discovery that primaquine was a trigger for haemolysis in G6PD patients, other drugs and
Red Cell Glycolysis and G6PD Deficiency2 Glucose Glucose 6-phosphate dehydrogenase deficiency impairs the ability of an erythrocyte to form NADPH, resulting in hemolysis
Glucose
Oxidant stress Certain drugs Infections Fava beans
Glucose 6-phosphate (G6P)
2 ADP
G6P
G6P
NADP+
Glucose 6-phosphate dehydrogenase
Glycolytic pathway
6-Phosphogluconate
2 ATP
NADPH + H+
2 GSH Glutathione reductase
H 2O 2 Glutathione peroxidase
GS-SG
2 H 2O
ERYTHROCYTE 2 Lactate
HMP
Table 1: Safe & unsafe drugs and chemicals for the use in G6PD deficient patients Drugs & chemicals likely to be UNSAFE in WHO Class I, II & III ¬¬ Dapsone ¬¬ Dimercaprol ¬¬ Henna ¬¬ Methylene Blue ¬¬ Naphthalene ¬¬ Nitrofurantoin ¬¬ Primaquine ¬¬ Toluidine Blue
Drugs & chemicals previously considered unsafe, but PROBABLY SAFE in therapeutic doses in WHO Class II & III patients (Safety unknown in Class I patients) ¬¬ Ascorbic acid (Vitamin C) ¬¬ Aspirin ¬¬ Chloramphenicol ¬¬ Chloroquine ¬¬ Ciprofloxacin* ¬¬ Co-trimoxazole* ¬¬ Glibenclamide ¬¬ Hydroxychloroquine* ¬¬ Isoniazid ¬¬ Isosorbide Dinitrate ¬¬ Mesalazine* ¬¬ Nalidixic Acid* ¬¬ Norfloxacin* ¬¬ Ofloxacin* ¬¬ Paracetamol ¬¬ Quinine ¬¬ Sulfacetamide* ¬¬ Sulfasalazine*
Drugs & chemicals GENERALLY CONSIDERED SAFE in usual therapeutic doses in WHO Class II & III (Safety unknown in Class I patients) ¬¬ Colchicine ¬¬ Diphenhydramine ¬¬ Doxorubicin ¬¬ Levodopa-Carbidopa ¬¬ Para-aminobenzoic acid (PABA) ¬¬ Sulfadiazine* ¬¬ Vitamin K and synthetic derivatives* * Some references consider these drugs as UNSAFE for all WHO classifications.4
Continued on page 4
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Sucroferric oxyhydroxide (Velphoro) for Hyperphosphatemia in Chronic Kidney Disease Sara-Jane Merlino, Epic Pharmacy Brisbane Private Sucroferric oxyhydroxide is an ironbased, calcium-free oral phosphate binder indicated in hyperphosphatemia for patients with chronic kidney disease undergoing dialysis.1 It prevents phosphate absorption by binding to dietary phosphate in the gastrointestinal-tract reducing serum phosphate concentrations.1 Sucroferric oxyhydroxide is available in a 500mg strength chewable tablet that must be chewed and not swallowed whole.2 The starting dose is 1500mg daily and may be titrated to a maximum total daily dose of 3000mg.2 It is best taken with food
G6PD – The Key to Red Blood Cell Survival Continued from page 3 chemicals have now been implicated. This list is continually updated and available on www.g6pd.org or www.g6pddeficiency.org and should be viewed by interested patients or health professionals.4 Care should be taken when interpreting the evidence as much of it is anecdotal and controversial. For instance, haemolysis previously attributed to certain drugs like aspirin is now thought to have been caused by the infections that the drugs were being used to treat. Other drugs such as sulfamethoxazole which is a component of the antibiotic co‑trimoxazole, modestly potentiates red blood cell destruction and therefore appears on some lists as being unsafe to use and other lists as safe to use in therapeutic doses. The WHO classification of G6PD deficiency is therefore also important when reflecting on drug safety as those
to minimise the absorption of dietary phosphate.2 The most common adverse effects reported are mild diarrhoea and discoloured faeces due to iron excretion.3 Clinical studies have demonstrated that the systemic absorption of iron from sucroferric oxyhydroxide is low, however it is contraindicated in haemochromatosis or other iron accumulation conditions. It interacts with alendronate, thyroxine and doxycycline.2 Sucroferric oxyhydroxide is recommended as second line therapy for hyperphosphatemia ineffectively controlled by calcium-based phosphate
drugs thought to be safe for individuals in Class III are potentially not for those with Class I deficiency.4 Table 1 identifies some of the drugs or chemicals that are safe or unsafe for use in G6PD deficient patients and is derived from references that demonstrate a definite drug associated haemolysis. The G6PD website (www. g6pd.org) however should always be consulted for up to date information.4 The variability in patient response to a drug or chemical is cause for much confusion. Other factors such as patient age, pharmacokinetics of the drug, the age and integrity of the red blood cell population and underlying illnesses such as infection, should all be considered before prescribing a potential trigger.1 Episodes of red blood cell haemolysis usually occur 24 to 72 hours after being exposed to the trigger. The red blood cells that are particularly susceptible to oxidative stress are the aging red blood cells that have the lowest levels
binders. It is a treatment option in hypophosphatemia where calcium is contraindicated.2 Sucroferric oxyhydroxide doesn’t deposit in bones like lanthanum or impair the absorption of lipid-soluble vitamins like sevelamer carbonate.4 Sucroferric oxyhydroxide’s benefits overall are its phosphatebinding capacity, tolerable adverse effect profile, minimal absorption and reduced tablet burden, which may increase medication compliance and enhanced patient health outcomes. References available on request.
of G6PD. When these are destroyed new red blood cells are produced, which have higher levels of G6PD and are not as sensitive to oxidative stresses. The haemolysis in this case is usually self-limiting and resolves within 8 to 14 days. The offending trigger is usually ceased and blood transfusions are rarely indicated. If however the G6PD deficiency is severe and red blood cell destruction is great, the acute haemolysis can lead to a severe anaemia which often requires a red blood cell transfusion.3 Unfortunately for G6PD deficient patients there is no cure. The disease is best managed by avoiding haemolysis triggered by the prohibited list of drugs, chemicals and foods. For this to occur, the patient would have had to have been screened for the disease or unfortunately encountered a prior haemolytic episode.1,3,4 References available on request.
If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.
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