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Drug-Induced Glucose Alterations Part 1: Drug-Induced Hypoglycemia
Drug-Induced Glucose Alterations Part 1: Drug-Induced Hypoglycemia
13.8% of all hospital admissions three- to fourfold increased risk of ulating hepatic glucose production.
for hypoglycemia were significantly hypoglycemia. Although the exact Suppression of peripheral sympa-
attributable to the use of ACE mechanism for its glucose-lowering thomimetic overactivity may also be
inhibitors (odds ratio 2.8 [95% effects is unknown, the hypoth- involved in blood glucose–lowering
CI 1.4–5.7]), but this was among esis involves an indirect increase in effects of ACE inhibitors.14
patients with diabetes concomitantly insulin sensitivity by increasing cir-
treated with insulin or oral antidia- culating kinine, which in turn leads Alcohol/Ethanol
betic agents for at least 1 year. to vasodilatation in the muscles and Hypoglycemia associated with
Another small study13 determined ultimately increased glucose uptake alcohol ingestion is a well-established
that ACE inhibitor use in people in muscle tissue. Bradykinin may also problem in patients with diabetes.
with diabetes was associated with a have a contributory role in downreg- Patients who are treated with anti-
Diabetes Spectrum Volume 24, Number 3, 2011 173
Pharmacy and Therapeutics
diabetic agents such as insulin and The proposed mechanism of tion.16 Alcohol may also indirectly
SUs (e.g., glyburide) are at higher alcohol-induced hypoglycemia in increase endogenous insulin secre-
risk for developing hypoglycemia, a fasting and intoxicated patient is tion, contributing to hypoglycemic
particularly those who have been primarily the inhibition of gluconeo- effects observed in individuals.17
previously fasting or who have a his- genesis along with depleted glycogen Furthermore, symptoms of hypogly-
tory of chronic abuse.15 stores as a response from starva- cemia can bear such a resemblance
174 Diabetes Spectrum Volume 24, Number 3, 2011
Pharmacy and Therapeutics
Table 4. Non-Diabetes
Table 4: Non-Diabetes Drugs Associated
Drugs Associated With Hypoglycemia
With Hypoglycemia 1,3,9,17,20,
continued
1,3,9,17,20
from p. 174
Quinolones • Ciprofloxacin Unknown; enhanced insulin Bacterial conjunctivitis, +
(Fluoroquinolone) • Gatifloxacin secretion appears to result bronchitis, community-
• Levofloxacin from blockade of ATP- acquired pneumonia,
• Moxifloxacin sensitive potassium channels gonorrhea, uncompli-
• Norfloxacin in pancreatic β-cells cated skin infections,
• Ofloxacin pyelonephritis, acute
sinusitis, urinary tract
infections
Pentamidine Cytolytic release of insulin Pneumocystis +++
pneumonia, cutane-
ous leishmaniasis,
trypanosomiasis, visceral
leishmaniasis
Salicylates • Aminosalicylic Increases insulin secretion Pain, fever, inflamma- +
acid and sensitivity; may alter tion, cerebrovascular
• Aspirin pharmacokinetic disposition accident, MI
• Choline magne- of SUs
sium trisalicylate
• Magnesium
salicylate
• Salsalate
+ Low probability of occurrence and/or low level of drug-induced hypoglycemia expected in patients.
++ Moderate-to-high probability of occurrence but degree of drug-induced hypoglycemia may or may not be clini-
cally significant.
+++ High probability of occurrence; drug-induced hypoglycemia is clinically significant.
to symptoms of mild alcohol intoxi- hypoglycemia. The catecholamine- insulin.21 Over time, patients become
cation that patients may be negligent mediated neurogenic hypoglycemic increasingly deficient in insulin as the
of the differences. Patients should be symptoms masked by this class pancreatic destruction progresses,
appropriately cautioned about close of medications include tremor eventually resulting in hyperglycemic
monitoring of blood glucose levels to and palpitations. Hunger, tremor, episodes. Within a matter of weeks
ensure the actual cause.15,17 irritability, and confusion may be to months, this consequential adverse
concealed as well. Sweating, how- effect can lead to the development of
β-blockers ever, remains unmasked and may be new-onset diabetes.9,17,20
β-blockers can cause or exacerbate the only recognizable sign of hypo-
hypoglycemia in some individu- glycemia in individuals treated with Quinolone (Fluoroquinolone)
als, either by worsening an already β-blockers.17,20 Antibiotics
present hypoglycemic episode Quinolones, commonly known as
or by delaying recovery time.17 Pentamidine fluoroquinolones, are widely used as
The mechanism responsible for Pentamidine is used in the treatment broad-spectrum antibiotics against
β-blocker–induced hypoglycemia of opportunistic infections associated community- and health care–asso-
involves inhibition of hepatic glucose with immunosuppression such as ciated infections. Incidences of
production, which is promoted by Pneumocystis pneumonia, although quinolone-induced hypoglycemia in
sympathetic nervous stimulation. In it is no longer considered a first-line the literature vary within the class,
addition, adrenergic counterregula- therapy because of its glucose-alter- but gatifloxacin has been associ-
tion is diminished, resulting in a ing adverse effects.9 Hypoglycemia is ated with having a greater effect on
reduction in glycogenolysis.17,18 the most common metabolic abnor- increasing insulin levels and reduc-
Non-cardioselective β-blockers mality observed within 5–14 days ing blood glucose compared to other
such as propranolol are more likely of initiating therapy and occurs in quinolones.1 In fact, the prescrib-
to cause hypoglycemia than cardio- about 6–40% of patients.17,20 ing information for gatifloxacin
selective ones such as atenolol and Pentamidine-induced hypogly- specifically states that diabetes is
metoprolol. Nevertheless, patients cemia is caused by an increase in a contraindication for use.22 The
on the latter should still be cautioned insulin secretion via a cytolytic prescribing information for other
about the potential for drug-induced response in the pancreas. Intravenous quinolones (e.g., ciprofloxacin, levo-
hypoglycemia.19 glucose or oral diazoxide at initiation floxacin, and moxifloxacin) include
Furthermore, β-blockers have the of therapy is often given in antici- information about altering serum
potential for masking symptoms of pation of this cytolytic release of glucose levels but only suggest cau-
Diabetes Spectrum Volume 24, Number 3, 2011 175
Pharmacy and Therapeutics
tion regarding their use in patients weeks, A1C was lowered by ≥ 0.5% 3
Dipiro JT, Talbert RL, Yee GC, Matzke
with diabetes. from baseline (P = 0.009). Patients GR, Wells BG, Posey LM: Pharmacotherapy:
A Pathophysiologic Approach. 6th ed.
The mechanism is unknown, but were concomitantly treated with diet Stamford, Conn., Appleton & Lange, 2005
it has been theorized that quino- and exercise alone, an insulin secre-
lones indirectly cause hypoglycemia tagogue, or a DPP-4 inhibitor, either
4
de Galen BE, Schouwenberg BJJW, Tack CJ,
Smits P: Pathophysiology and management
through blockade of adenosine 5′tri- as monotherapy or in combination. of recurrent hypoglycemia and hypoglyce-
phosphate (ATP)-sensitive potassium Other studies have shown high-dose mic unawareness in diabetes. Neth J Med
channels in the pancreatic β-cells aspirin therapy (e.g., 4–7 g/day) to 64:269–279, 2006
that regulate calcium influx. This indirectly enhance insulin sensitivity 5
McCrimmon RJ, Frier BM: Hypoglycemia,
enhances insulin release in a dose- in liver and muscle through reduced the most feared complication of insulin
dependent manner.23 rates of lipolysis and lowered levels of therapy. Diabetes Metab 20:503–512, 1994
Furthermore, because quinolones plasma fatty acid.27 6
Greco D, Angileri G: Drug-induced severe
are excreted primarily by the renal Although salicylates have been hypoglycemia in type 2 diabetic patients
route, patients with renal insuf- reported to lower blood glucose con- aged 80 years or older. Diabetes Nutr Metab
ficiency may be at higher risk for centrations, results are conflicting 17:23–26, 2004
developing hypoglycemia if accu- and warrant further safety investi- 7
Yang S, Zhou Y, Hu D, Nie X, Liu Y, Hua Q,
mulation occurs, particularly in the gations. Nonetheless, the potential Wang X, Li H: Association between admis-
elderly.1,24 Although incidences of for salicylate-induced hypoglycemia sion hypoglycemia and in-hospital and 3 year
mortality in older patients with acute myocar-
quinolone-induced hypoglycemia should be considered in patients, dial infarction. Heart 96:1444–1450, 2010
have mostly been reported in older particularly those administered high
adults with diabetes concomitantly
8
Murad MH, Coto-Yglesias F, Wang AT,
doses or taking concurrent insulin or
Sheidaee N, Mullan RJ, Elamin MB, Erwin
taking insulin or SUs, the adverse oral insulin secretagogues. PJ, Montori VM: Drug-induced hypoglycmia:
effect has been reported to develop a systemic review. J Clin Endocrinol Metab
in individuals without a history of Summary 94:741–745, 2009
diabetes.1 Numerous pharmacological agents 9
Thomson Reuters Healthcare: Micromedex
that are commonly used in patients Healthcare Series. Available online from
Salicylates with or without diabetes have the http://www.micromedex.com/products/hcs.
In the early 1900s, salicylates potential to alter serum glucose Greenwood Village, Colo., Thomson Reuters
were considered a treatment for levels. Although drug-induced Healthcare, 2011
diabetes because of their poten- hypoglycemia is often mild, it is a 10
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relatively short-lived.25 Limited by comparative effectiveness and safety of oral
hospitalizations, excessive costs,
medications for type 2 diabetes mellitus. Ann
their associated adverse effects (i.e., and significant mortality rates. A Intern Med 147:386–399, 2007
gastrointestinal [GI] bleeding) as comprehensive understanding and
a blood glucose–lowering agent,
11
Ferriere M, Lachkar H, Richard JL, Bringer
awareness of the drug mechanisms J, Orsetti A, Mirouze J: Captopril and insulin
salicylates are now used primarily as responsible for lowering serum sensitivity [letter]. Ann Intern Med 102:134,
analgesic, anti-inflammatory, anti- glucose concentrations may allow for 1985
pyretic, and antiplatelet agents.9 better prediction of drug interactions Herings RMC, de Boer A, Stricker BHC,
12
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for GI bleeds, salicylates have also the implementation of more individu- associated with the use of inhibitors of
been recognized to induce hypogly- alized, rational, and safe therapies angiotensin converting enzyme. Lancet
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13