Adverse Drug Reactions

Management of Gout (Medications)

October 25, 2012 Adverse Drug Reactions, Drug Informatics, Pharmacotherapy No comments , , , ,

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are the drugs of choice in most patients with acute gout who do not have underlying health problems. However, aspirin should not be used because it can alter uric acid levels and potentially prolong and intensify an acute attack.

Avoid NSAIDs in patients who have a history of peptic ulcer disease or GI bleeding, patients with renal insufficiency, patients with abnormal hepatic function, patients taking warfarin (selective COX-2 inhibitors can be used but used cautiously), and patients in the intensive care unit who are predisposed to gastritis. In patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.

NSAIDs are prescribed at full dosage for 2-5 days to control the acute attack, and the dose is reduced to approximately one half to one fourth of that amount once the acute attack is controlled. Taper the dose down over approximately 2 weeks. But the consistent low-dose of NSAIDs used for 6-24 months may help to prevent the occurring of acute gout attack during the chronic lowering uric acid treatment.

Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.


Although colchicine was once the treatment of choice for acute gout, it is now a second-line approach because of its narrow therapeutic window and risk of toxicity.

Colchicine therapy must be initiated within 24 hours of onset of the acute attack to be effective. Dosing recommendation for colchicine in acute gout therapy have been modified in recent years because of an increased awareness of its toxicities. The most recent recommendations have been trending toward lowered daily and cumulative doses. The favored regimen is low-dose colchicine 1.8 mg total over 1 hour (1.2 mg PO initially then 0.6 mg q1hr, total not to exceed 1.8 mg over 1 hour-period).

Colchicine should not be used if the glomerular filtration rate (GFR) is less than 10 mL/min, and the dose should be decreased by at least half if the GFR is less than 50 mL/min. Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.

For prophylaxis the dose of colchicine is 0.6 mg bid or lower. In patients with renal insufficiency, this dose may need to be decreased to daily or overy-other-day administration. Even in prophylactic dose, colchicines can cause marrow toxicity and neuromyopathy in the setting of renal insufficiency. Long-term use of colchicine can lead to a muscle weakness associated with elevated levels of creatine kinase due to a drug-induced neuromyopathy, particularly in patients with renal insufficiency.


Corticosteroids can be given to patients with gout who cannot use NSAIDs or coclchicine, but adrenocorticotropic hormone (ACTH) would be preferred. Steroids can be given orally, intravenously, intramuscularly, intra-articularly, or indirectly via ACTH.

ACTH 40 IU can be given to induce corticosteroid production by the patient’s own adrenal glands. Such a regimen dose not depend on the patient to properly taper prednisone. Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.

Intra-articular, long-acting (depot) corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids.


Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Therefore, it should be used in patients who overproduce uric acid. It is the most effective urate-lowering agent. However, alcohol can interfere with effectiveness of allopurinol.

Approximately 3-10% of patients taking allopurinol develop dyspepsia, headache, diarrhea, and/or pruritic maculopapular rash. Less frequently, patients taking allopurinol can develop allopurinol hypersensitivity, which carries a mortality rate of 20-30%. Features of allopurinol hypersensitivity include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids are often used to treat allopurinol hypersensitivity.

Allopurinol hypersensitivity is more likely to occur in patients with renal insufficiency, patients who are taking a diuretic, and patients begun on 300 mg of allopurinol. Although allopurinol hypersensitivity is more common (although still rare) in patients with renal insufficiency, this effect dose not appear to be dose-related. Thus, a slow and careful titration of allopurinol dosing sufficient to achieve uric acid levels of less than 6 mg/dL is also recommended in these patients.

Allopurinol is also associated with the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after beginning allopurinol. The underlying mechanism is thought to be a cell-mediated immunity to allopurinol and its metabolites. Although occurrence is 0.4%, the rate of organ failure and death is high. Treatment is with intravenous N-acetyl cysteine and steroids. Allopurinol should be discontinued in patients who develop a rash.

In most patients, start at 100 mg per day (50 mg in patients with renal insufficiency) and adjust the dose monthly according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved.

While adjusting the dosage of allopurinol in patients who are being treated with colchicine and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

Update from Medscape Reference at on Sep 6th 2013.


Pegloticase is a pegylated uric acid–specific enzyme that is a polyethylene glycol conjugate of recombinant uricase. It achieves its therapeutic effect by catalyzing oxidation of uric acid to allantoin, thereby lowering serum uric acid levels. Pegloticase is indicated for gout in adults refractory to conventional therapy (ie, when serum uric acid levels have not normalized and either signs and symptoms are inadequately controlled with xanthine oxidase inhibitors or uricosurics at maximum appropriate doses or xanthine oxidase inhibitors are contraindicated).

The dosage is 8 mg IV every 2 weeks. Complications include anaphylaxis, infusion reactions, flare of gout attacks in 63-86% of patients and nephrolithiasis in 13-14%, along with arthralgias, nausea, dyspepsia, muscle spasms, pyrexia, back pain, diarrhea, and rash.[134, 135] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a contraindication.[135]

Systemic Therapy for Bone Metastases

August 24, 2012 Adverse Drug Reactions, Drug Informatics, Hematology, Pharmacology, Therapeutics No comments , , ,

zoledronic acid

Accelerated bone loss in patients with cancer is a frequent problem that may result from [1]invasion of the cancer to bone, [2]paraneoplastic tumor proteins, and/or [3]hormonal therapies utilized for cancer treatment.

  • Invasion of the cancer to bone;
  • Paraneoplastic tumor proteins;
  • Hormonal therapies utilized for cancer treatmen.

Invasion of cancer to bone is common complication in patients. The proportion of cancer invading to bone is 20% to 25% in kidney cancers, 65% to 75% in breast and prostate cancers, and almost all patients (70% to 95%) with multiple myeloma.

Mechanism of Bone Metastases

  1. Metabolically active tumor cells invade and populate bone and secrete growth factors that affect bone resorption and formation by stimulation of osteoclasts, cells that destroy bone by attacking the mineralized bone matrix.
  2. On the other hand osteoclasts also secrete growth factors that induce tumor cells in the bone to grow, spread, and stimulate the activity of osteoblasts, cells responsible for the formation of bone. However, osteoblastic activity creates new bone formation away from the sites of osteolytic bone resorption. So weakened areas are not strengthened by osteoblastic activity.
  3. Also, osteoblasts release receptor activator of nuclear factor κB ligand (RANKL), a key mediator of osteoclast formation, function, and survival, which is one of the mechanisms of metastatic bone disease.

Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both ostelytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy.

  • Pathological fractures;
  • Hypercalcemia;
  • Spinal cord compression;
  • The need for surgical intervention and radiation therapy.

Untreated patients with bone metastases are at risk for multiple SREs within a single year, ranging from 1.5 events for prostate cancer to 4.0 for breast cancer.

Treatment Agents

Now two types of agents are used to treat bone metastases – bisphosphonates and denosumab.


Bisphosphonates are unique drugs with an affinity for bone mineral matrix with the ability to inhibit bone resorption. Bisphosphonates decrease bone resorption and increase mineralization by entering osteoclasts and inhibiting farnesyl diphosphate synthase, a key enzyme in the biosynthetic mevalonate pathway.

Bisphosphonates may also affect bone resorption through the inhibition of osteoclast precursor maturation, induction of apoptosis in mature osteoclasts, inhibition of tumor cell adhesion to bone, and inhibition of inflammatory cytokine production.

Nitrogencontaining bisphosphonates (N-BPs) have the greatest antiresorptive activity. Based on in vitro studies, zoledronic acid is the most potent aminobisphosphonate and is the only intravenous bisphosphonate found to be effective in all types of metastatic bone lesions.

Bisphosphonates also have a potential antitumor effect. Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.

However data from the FDA and the United Kingdom showed the issue of potential risk of esophageal cancer with oral bisphosphonate use was raised. The FDA recently announced plans to continue review of the conflicting studies.

Safety and efficacy data of intravenous bisphosphonates in the metastatic setting are predominantly limited to 24 months of treatment. The most frequently reported side effects from intravenous bisphosphonates are fever and myalgias, which may occur in up to 55% of patients, typically within 12 hours of the initial infusion. Antiinflammatory agents may easily provide relief. Diarrhea and gastric irritation may develop with the oral bisphosphonates ibandronate and clodronate, which are not approved in the management of bone metastases in the United States. Electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hypomagnesemia, and hypermagnesemia, are rarely reported with intravenous bisphosphonates. Other condition such as  vitamin D deficiency, hypoparathyroidism, hypomagnesemia, or use of medication such as interferon, aminoglycosides, or loop diuretics may provoke these abnormalities. (more…)

Gout and the Antihypertensives

August 4, 2012 Adverse Drug Reactions, Cardiology, Therapeutics 1 comment , , , , , ,

The inflammatory arthritic condition of gout.

Gout, the inflammatory arthritic condition triggered by crystallization of uric acid within the joints, has risen in the United States. A research studied by Dr. Choi (Hyon K. Choi, MD, DrPH) and his colleagues shown that 74% of US gout patients also have hypertension. Dr. Choi’s group also has shown that hypertension is an important independent risk factor for gout. In patients with hypertension, the incidence of gout has been calculated as 3 times higher than in normotensive patients.

Simplistic speaking, much of this added risk is attributed to the use of diuretics, which are associated with increased serum uric acid levels. But hypertension itself is associated with increased risk of gout. Not only diuretics, but also other nondiuretic classes of antihypertensive drugs have been shown to affect serum uric acid levels.

Generally, with the use of diuretics, beta-blockers, ACEI, and non-losartan angiotensin II receptor blockers (ARBs), the risk of gout incresed.

However as antihypertensive drugs, calcium channel blockers (CCBs) and losartan (a kind of ARBs), are associated with reduced risk of gout.

In an editorial published alongside the study report, Luis M. Ruilope, MD, (Hospital 12 de Octubre and University Autonoma, Madrid, Spain) noted that a reduction in serum uric acid “as well as reducing incident gout, could also improve the cardiovascular and renal prognosis of patients with hypertension.” Thus, to control the serum uric level is important for hypertensive patients.

A number of variables affect serum uric acid levels and the risk of gout, including many life style factors such as adiposity, represented by BMI; dietary factors, particularly alcohol consumption, fructose-rich beverages such as sugary sodas, and a purine-rich diet, particularly animal sources of purine such as red meat or seafood. And in right here, finally, drugs can cause increased risk of gout.

The mechanism of increased risk of gout with hypertension is that as blood pressure elevates, serum uric acid concentration increases, which appears to be a dose-response relationship. Also urate excretion is lower in hypertensive patients than in normotensive individuals. Reduced renal blood flow with increased renal and systemic vascular resistance may also contribute to elevated serum uric acid levels. eventually leading to an increased risk of gout.

The mechanism of increased risk of gout with antihypertensive drugs are variable. Diuretics, the loop and thiazide-type diuretics, can increase serum uric acid levels and the risk of gout. The mechanism of the nondiuretic antihypertensive drugs include ACE inhibitors, non-losartan ARBs are unknown. But clinical trials has shown beta-blockers can increase serum uric acid levels slightly. the mechanism of beta-blockers is unknown neither.

Here I find some data. With beta-blockers, the risk of gout was 48% higher in people with hypertension. ACEIs also have the identical effect. But there is an exception – the diuretics.

Fortunately, specific antihypertensive drugs contribute to the reduce risk for gout. The unique ARB, losartan, lowered uric acid levels in one clinical trial. Bench studies have shown that losartan causes increased uric acid secretion (uricosuria) by inhibiting urate/anion transport in brush-border cells of the renal proximal tubules through inhibition of urate transporter 1 (URAT 1). That is losartan inhibits uric acid reabsorption, causing uricosuria, eventually driving down blood uric acid levels and the reduced risk of gout.

Also CCBs including dihydropyridines and nondihydropyridines have the ability to decrease the risk of gout. The mechanism is unkown. For people with hypertension, taking CCBs lowered their risk of gout by 13% compared with people with hypertension who were not taking a CCB.

To rudece the risk of gout in hypertensive patients, we couldn’t avoid these antihypertensive drugs such as ACEIs, ARBs, or diuretics. Because these patients benefits from these drugs. Thus when the antihypertensive regimen contains drugs increasing risk of gout, we may add another antihypertensive drug that decreases the risk of gout. With the use of the protective drugs, like CCB or losartan, the risk should become even lower.

Clinical Report-Drug Interaction Between Fluoxetin and Mirtazapine

July 23, 2012 Adverse Drug Reactions, Drug Interactions, Entertainment 55 comments , , ,

Clinical Case Report


Fluoxetin and Mirtazapine.

Date: July 8 2012

Place: Outpatient Pharmacy, 416 Hospital

Abstract and Introduction:

On the afternoon, July 8 2012 one male patient came to the outpatient pharmacy to take his drug. The phyisican prescribed fluoxetin accompanied by mirtazapine. I checked these two drugs in drug interaction checker and drug interactions were found between fluoxetine and mirtazapine – Potential for dangerous interaction ( may causes serotonin syndrome, although serotonin is rare but is life-threatening). I suggested the patient take these two drugs carefully. I told the man if he have the symptoms or signs of serotonin syndrome he should withdraw both drug immediately and back to hospital for further care if necessary.


The Neurology Clinics prescribled fluoxetine accompanied by mirtazapine  to a middle-age man. The dosage and frequency for fluoxetine is 20mg po Qd meanwhile that for mirtazapine is 30mg po Qd.

I checked these two drugs in drug interaction checker and a drug interaction was found between fluoxetine and mirtazapine – Fluoxetine and mirtazapine both increase serotonin levels, potential for dangerous interaction ( may causes serotonin syndrome, although serotonin is rare but life-threatening).

So due to this drug interaction, when I was dispensing these two to him, I asked him whether he was also taking or had recently taken any other psychotropic medications such as antidepressants, MAOIs, SSRIs or some drugs such as analgesics and so on, which also increase serotonin levels and may cause serotonin syndrome if they are coadministered. He told me negative. So I told him that he could take these two medications in combination, but should take with caution due to the drug interaction between fluoxetine and mirtazapine. And the most important is that I taught him how to identify serotonin syndrome. Simply that the general symptoms and signs of serotonin syndrome are clonus, agitation or diaphoresis, tremor and hyperreflexia or hypertonia, temperature above 100.4°F (38° C) and I said if he have any symptoms or signs of serotonin syndrome both drugs should be withdrawed immediately and he should go back to hospital for further care if necessary, I told him.

Finally the patient told me he knew what he should and took both drugs home.


Serotonin is a neurotransmitter that is synthesized from the amino acid L-tryptophan. Synthesis is necessary in the central and peripheral nervous system because serotonin cannot cross the blood-brain barrier. Once synthesized, serotonin is either stored in neuronal vesicles or metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid. Serotonin binds 1 of 7 postsynaptic 5-hydroxytryptophan (5-HT) receptors. The hyperstimulation of the 5-HT receptors in the brain and/or spinal cord is the cause of serotonin syndrome. So what is serotonin syndrome? Serotonin syndrome, characterized by mental status changes, neuromuscular dysfunction, and autonomic instability, is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Serotonin syndrome is a potentially life-threatening set of symptoms caused by serotonin toxicity, and usually involves a combination of psychotropic medications that increase serotonergic transmission. That means specific drug interactions can be the reason for serotonin syndrome. Serotonin syndrome can ensue after the addition of a second serotonergic drug to an existing drug regimen or with administration of a serotonergic drug before allowing an inadequate washout period after discontinuation of another serotonergic drug. Potential mechanisms and corresponding agents of serotonin syndrome include:

  1. Increasing production of serotonin by providing increased amount of precursors – L-tryptophan-containing substances;
  2. Prevention of metabolism of stored serotonin – Monoamine oxidase inhibitors (MAOIs);
  3. Increased release of stored serotonin – Amphetamine, cocaine, fenfluramine, methylenedioxymethamphetamine (MDMA or ecstasy), or meperidine;
  4. Prevention of reuptake of serotonin released into the synapse – SSRIs, tricyclic antidepressants (TCAs), MDMA, dextromethorphan, meperidine, or St John’s Wort;
  5. Direct stimulation of serotonin receptors – Buspirone, lysergic acid, diethylamide (LSD);
  6. Unknown mechanism – Lithium.

I summarize the drugs which are implicated in serotonin syndrome. They are in  Table 1.



Amphetamines and their derivativesEcstasy Dextroamphetamine, Methamphetamine and Sibutramine
AnalgesicsCyclobenzaprine, Fentanyl, Meperidine, Tramadol
Antidepressants/Mood stabilizersBuspirone, Lithium
Monoamine Oxidase InhibitorsPhenelzine
Serotonin-Norepinephrine Reuptake InhibitorsVenlafaxine
Serotonin 2A Receptor BlockersTrazodone
St. John’s Wort
Tricyclic Antidepressants
AntiemeticsMetoclopramide, Ondansetron
Antimigraine Drugscarbamazepine, ergot alkaloids, triptans, and valproic acid

Table 1 Drugs that are potential to serotonin syndrome.

Other drugs if used in combination that may cause serotonin syndrome include cocaine, dextromethorphan, linezolid, l-tryptophan, and 5-hydroxytryptophan. (more…)

Maternal Antidepressant Use May Promote Pregnancy-Induced Hypertension

July 19, 2012 Adverse Drug Reactions, Pregnancy Medicine 2 comments , , , , ,

Today I read an article that disscusses the adverse effects of the antidepresants use during pregnancy. It says that when using antidepressant during pregnancy will causes hyperstension. The article is below.

One thing I want to emphase is that according to the authors of this study in the article, 4% to 14% of pregnant women are receiving antidepressants. Indeed, depression is one of the most commmon chronic illnesses among pregnant women. But should we use antidepressants during pregnancy? I check one of  antidepresants – Paroxetine – one of the SSRIs on medscape. Paroxetine belongs to Pregnancy Category: D and has Teratogenic Effects: Paroxetine increases the risk of congenital malformations, particularly cardiovascular malformations.

As above I think pregnancy should be one of the contraindications of this SSRI due to the teratogenic effects. Maybe all SSRIs have the effect of teratogenicity during pregnancy, but 4% to 14% of pregnant women are receiving antidepressants, maybe also the SSRIs such as Paroxetine. So anyone can tell me in U.S. do the pregnant women receive SSRIs to treat depression?

Clinical Context

Depression is one of the most common chronic illnesses among pregnant women, with a prevalence of approximately 20%. According to the authors of the current study, 4% to 14% of pregnant women receive antidepressants, and these medications are not without adverse effects. The use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy is most associated with a modest increase in the risk for congenital abnormalities, including heart defects.

Less data suggest serious adverse events of antidepressants on the pregnancy itself. However, antidepressants generally increase levels of circulating serotonin, which can, in turn, raise blood pressure. Some previous research has suggested that antidepressants can increase the risk for pregnancy-induced hypertension and preeclampsia during pregnancy. The current study by De Vera and Bérard uses a large patient database to further investigate the association between pregnancy-induced hypertension and antidepressants.

Study Synopsis and Perspective

Women who use antidepressants while pregnant have an increased risk of developing pregnancy-induced hypertension, new research shows.

The increased risk is beyond the risk that could be attributed to their depression or anxiety disorders, Mary A. De Vera, PhD, from the University of Montreal, and Anick Bérard, PhD, from Sainte Justine Research Center, Montreal, Quebec, Canada, write.

“Antidepressants are used widely during pregnancy, up to 14% of pregnant women use them,” Dr. Bérard told Medscape Medical News. “Our study adds one more piece to the puzzle with regard to the risk of using antidepressants during pregnancy.”

The study is published online March 22 in the British Journal of Clinical Pharmacology.

Do Not Stop Meds

SSRIs are the main antidepressants in use today, and serotonin is a vasoconstrictor and also directly affects diastolic blood pressure, although the mechanism of action for this is not very well understood, Dr. Bérard noted.

In this study, the researchers analyzed data from the Quebec Pregnancy Registry and compared 1216 women who had been diagnosed with pregnancy-induced hypertension, with or without preeclampsia, who had no history of hypertension before they became pregnant, with 12,160 matched control individuals.

They found that among the participants with pregnancy-induced hypertension, 45 (3.7%) had used antidepressants during pregnancy, compared with 300 (2.5%) of the women in the control group (odds ratio [OR], 1.52; 95% confidence interval [CI] 1.10 – 2.09).

Antidepressant use during pregnancy was associated with a 53% increased risk for pregnancy-induced hypertension (OR, 1.53; 95% CI, 1.01 – 2.33). Use of SSRIs was associated with a 60% increased risk (OR, 1.60; 95% CI, 1.00 – 2.55); of the SSRIs, paroxetine was associated with the greatest risk for pregnancy-induced hypertension (OR, 1.81; 95% CI, 1.02 – 3.23).

“It is very important for physicians and women to discuss the risks and benefits of antidepressants before prescribing,” said Dr. Bérard.

“Close monitoring needs to be done, because there could be benefits, and there can also be risks. The message isn’t as simple as telling pregnant women to stop taking antidepressants.

“The decision has to be made one woman at a time. Anyone affected by this study should not stop taking their prescribed medication but seek a consultation with their doctor if they are concerned,” she said.

“Important” Limitations

Linda Chaudron, MD, associate chair for clinical services in the Department of Psychiatry at the University of Rochester Medical Center in New York, said the study adds to recent studies that have explored the hypothesis of an association between antidepressant use and pregnancy-induced hypertension. (more…)