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Case Study Pair Old New February
Case Study Pair Old New February
2. What could be given to treat this patient? which is induced by statins. The incidence of mild muscle pain with statins is
3. What is the danger if the patient is not treated? between 2% and 7% in clinical trials. The onset varies from a few weeks to over 2
Answers years after starting treatment, the incidence is dose-related and the severity ranges
1. Methanol Poisoning from mild aches to severe pain, causing reduced mobility. Older people, who may
2. Ethanol - Rationale for ethanol in methanol poisoning: Competes for metabolism have reduced renal function or liver function, are at greater risk of statin-induced
myopathy. Diltiazem can inhibit the metabolism of simvastatin due to its actions on
by alcohol dehydrogenase to reduce the production of toxic metabolites of
cytochrome P450 isoenzyme CYP3A4, thereby increasing the risk of myopathy.
methanol.
Statin-induced myopathy ranges from mild myopathies and myalgias, to myositis,
3. The toxicity of methanol is primarily mediated by its metabolites. Methanol is
to rare cases of potentially life-threatening rhabdomyolysis, in which muscle cell
metabolized by alcohol dehydrogenase to formaldehyde and subsequently to
walls are disrupted and the contents leak into the systemic circulation. Muscle pain
formic acid, the most likely cause of major organ toxicity. Formic acid inhibits
in patients taking statins should, therefore, always be taken seriously.
cytochrome oxidase activity, resulting in tissue hypoxia and lactic acid production. 2. The problem is associated with all drugs in the class. Although simvastatin and
The metabolic acidosis that occurs in methanol overdose is a result of the atorvastatin, the most widely prescribed, are both lipophilic and metabolised by
combination of formic acid and lactic acid that is produced. The most characteristic cytochrome P450 3A4 and, therefore, may be most likely to cause muscle pain,
symptom in methanol poisoning is visual disturbances with blurred vision and a there is no reliable comparative data on different statins.
sense of being in a snowstorm. Isopropyl alcohol and ethylene glycol similarly are 3. Creatinine kinase (CK) levels should have been measured before initiating statin
metabolized by alcohol dehydrogenase to toxic metabolites. Unfortunately, the therapy, but regardless of whether or not this was done, a CK level should be
toxic metabolites of all of these solvents can cause permanent neurologic damage, measured now, plus liver function tests. Mr KM's primary care doctor should be
contacted to inform him about the suspected ADR and the patient encouraged to
blindness, coma, and death. In these clinical settings ethanol can be used
report the ADR via the Yellow Card Scheme. It may be appropriate to discontinue
therapeutically. It is given by continuous IV infusion to compete for metabolism by
or reduce the dose of the simvastatin, depending on the result of the CK level and
alcohol dehydrogenase. With hemodialysis, this can help to reduce the ongoing
the severity of the symptoms. The problem may not resolve immediately on
production of toxins. Sodium bicarbonate can be given to help correct the
discontinuation. Grapefruit juice can increase blood levels of simvastatin and high
metabolic acidosis. Fomepizole, another available, very costly (~$4000 per patient)
alcohol intake increases the risk of myopathy, so the pharmacist should also warn
inhibitor of alcohol dehydrogenase is also available.
Mr KL about avoiding these.
glucosamine have been submitted to U K, Australian and U S regulators. Additional
Case 5.2 cases have been reported in the literature. While there is no known mechanism and
A 39-year-old male taking varenicline for smoking cessation reports that he has been suffering no formal interaction studies, the published cases and spontaneous reports are
from vivid dreams and has become increasingly aggressive towards his family. Last night he sufficient evidence to suggest a potential interaction. Given the wide use of
had a major argument with his wife. His wife mentioned he hadn't been the same since he glucosamine, the interaction may be rare, although under-reporting is common.
started the varenicline and he would like to know if this was a possible cause. Assessment of this individual case requires further questioning to eliminate other
Questions confounding factors such as changes in diet or adherence issues.
1. Is varenicline a possible cause of his vivid dreams and aggression? 2. Interactions with, or adverse reactions to, complementary and alternative remedies
2. Is this a reportable adverse drug reaction? can be reported to spontaneous reporting schemes, such as the Yellow Card
Answers Scheme. Collation of such reports allows regulators to gather further information on
1. Varenicline has been associated with neuropsychiatric ADR s, including depression, the suspected reaction, and any susceptibilities that may in time provide useful
suicidal thoughts, suicidal behaviour and aggression. Vivid dreams and other sleep information to other users.
disorders have also been reported. Prescribers have been warned that such
reactions have been reported. Assessing the cause of this reaction is difficult, since
Case 4.4
smoking cessation itself is associated with exacerbations of underlying psychiatric A 79-year-old man presented to hospital with a 3-day history of increasing confusion and
illness and the risk of symptoms of depression. As varenicline dosing starts 12 collapse. He had a history of chronic lumbosacral pain, treated with oxycodone 10 mg twice
weeks before stopping smoking, a key question is how long the patient has been daily and amitriptyline 75 mg daily. Five days before hospital admission he had been
taking the drug, and if the symptoms appeared before the smoking cessation date. prescribed tramadol 100 mg four times daily for worsening sciatica. On admission the patient
2. If a health professional considers that a patient's symptoms are a possible ADR to a had a Glasgow Coma Scale of 11 and he was delirious and hallucinating. There were no focal
newer drug, then they should be reported to regulatory authorities (in the UK, this neurological signs. Over the next 2 days he became increasingly unwell, confused and sweaty
would be through the MHRA's Yellow Card Scheme). Only a suspicion is necessary with pyrexia and muscular rigidity. Biochemical tests showed a metabolic acidosis (base deficit
to report a reaction, not proven causality. I n the case of intensively monitored of 10.7) and an elevated creatine kinase level of 380 IU/L. There was no evidence of infection.
medicines (identified by an inverted black triangle in the BNF), any reaction, no At this stage a diagnosis of probable serotonin syndrome was made.
matter how trivial should be reported. Patients can also report directly to regulatory Questions
authorities in some countries, including the U K. Neuropsychiatric reactions such as 1. What is serotonin syndrome and what drugs are most commonly associated with it?
this are commonly reported by patients. 2. How is serotonin syndrome managed?
Answers
Case 5.4 1. Serotonin syndrome is often described as a clinical triad of mental status changes,
55-year-old woman attending a warfarin out-patient clinic has a raised INR. On questioning it autonomic hyperactivity and neuromuscular abnormalities. However, not all these
is discovered that she has recently started taking glucosamine for muscle aches for the last 2 features are consistently present in all patients with the disorder. Symptoms arising
weeks. from a serotonin excess range from diarrhoea and tremor in mild cases to delirium,
Questions neuromuscular rigidity, rhabdomyolysis and hyperthermia in life-threatening cases.
1. What is the likelihood that glucosamine was responsible for the rise in the INR ? Disturbance of electrolytes, transaminases and creatine kinase may occur. Clonus is
2. Should this reaction be reported to regulatory authorities? the most important finding in establishing the diagnosis of the serotonin syndrome.
The differential diagnosis includes neuroleptic malignant syndrome, sepsis, hepatic
Answers encephalopathy, heat stroke, delirium tremens and anticholinergic reactions.
1. Glucosamine is a popular supplement purchased for joint health. It is commonly Serotonin syndrome may not be recognised in some cases because of its protean
used by older patients. Spontaneous reports of interactions between warfarin and manifestations. A wide range of drugs and drug combinations has been associated
with the serotonin syndrome, including MAOIs, tricyclic antidepressants, SSRIs,
opioids, linezolid and 5HT1-agonists. Tramadol is an atypical opioid analgesic with
partial antagonism and central reuptake inhibition of serotonin (5HT) and
noradrenaline. At high doses it may also induce serotonin release. Tramadol is
reported as causing serotonin syndrome alone (in a few case reports) and in
combination with SSRIs, venlafaxine and atypical antipsychotics.
2. Management of the serotonin syndrome involves removal of the precipitating drugs
and supportive care. Many cases typically resolve within 24 h after serotonergic
drugs are stopped but symptoms may persist in patients taking medicines with
long half-lives or active metabolites. The 5HT2A-antagonist cyproheptadine and
atypical antipsychotic agents with 5HT2A-antagonist activity, such as olanzapine,
have been used to treat serotonin syndrome, although their efficacy has not been
conclusively established.