Appalachian College of Pharmacy Metformin Associated Lactic Acidosis Discussion Answer this forum discussion prompt. I only need 2 paragraphs for each prom

Appalachian College of Pharmacy Metformin Associated Lactic Acidosis Discussion Answer this forum discussion prompt. I only need 2 paragraphs for each prompt.

Prompt 1: Before we get too far away from the Acid Base Calculations and discussions- I offer a few clinical case presentations that we deal with occasionally in the hospitalized patient. What do you think? Couple of drugs that can cause acid base disorders. Look at the case presentations of the propylene glycol and benzodiazepines- pretty subtle.

Prompt 2: Loop diuretic resistance is a common clinical concern in patients that are over exposed to the loop diuretics: what do you think and how do you maintain naturesis? Do some research for this prompt and site your source. M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 65 ( 20 1 6 ) 2 0–29
Available online at www.sciencedirect.com
Metabolism
www.metabolismjournal.com
Reviews
Metformin-associated lactic acidosis: Current
perspectives on causes and risk
Ralph DeFronzo a , G. Alexander Fleming b , Kim Chen c , Thomas A. Bicsak c,?
a
b
c
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Kinexum LLC, Harpers Ferry, WV, USA
Elcelyx Therapeutics, Inc., San Diego, CA, USA
A R T I C LE I N FO
AB S T R A C T
Article history:
Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus,
Received 24 June 2015
some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other
Accepted 5 October 2015
drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent
Keywords:
metformin concentrations (as occur in individuals with renal impairment) and a secondary event
manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma
Metformin
or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or
Drug mechanism
hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As
Lactic acidosis
these secondary events may be unpredictable and the mortality rate for MALA approaches 50%,
MALA
metformin has been contraindicated in moderate and severe renal impairment since its FDA
Renal impairment
approval in patients with normal renal function or mild renal insufficiency to minimize the
potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis
in clinical practice has proved to be very low ( 5 mg/L, elimination may be prolonged [20].
4.
Risk Factors for MALA
Owing to the multiple and often nonspecific signs and
symptoms of MALA, as well as the potential impact of other
conditions and medications that can predispose a patient to
lactic acidosis, MALA can be difficult to predict or diagnose
[21–23]. This is true especially in the absence of knowing the
circulating metformin concentration in a patient presenting
with symptoms [24]. However, it is known that MALA occurs
when there is an imbalance between increased lactate
production and impaired metabolism/reduced clearance.
Metformin plasma levels > 5 ?g/mL are generally found
when metformin is implicated as the cause of lactic acidosis
[6]. Such sustained very high elevations in plasma metformin
concentrations (therapeutic range < 2 ?g/mL [19]) usually are observed in individuals with poor renal function (i.e., reduced metformin clearance), impaired hepatic metabolism (i.e., reduced lactate clearance) [25,26], and/or in the presence of increased production (i.e., sepsis, CHF, reduced tissue perfusion, or anoxia). Although not contraindicated for metformin use in either the US or other countries, other conditions that may increase the risk of lactic acidosis include severe dehydration, shock, alcohol use, hypoxic states, sepsis, and advanced age (because of age-related decline in renal function and increased risk for acute renal failure and other catastrophic medical conditions) [6,8,27–29]. However, MALA can occur in patients with even mild renal dysfunction [30] and patient outcome seems to be correlated with severity of the underlying disease, highlighting the need for judicious use of metformin even in otherwise lower-risk patients. MALA is more likely to occur in patients who acutely develop renal impairment from dehydration, vomiting or diarrhea, surgery, etc., especially in elderly subjects who have a reduced glomerular filtration rate [31–38]. Dehydration can cause acute renal failure and reduce metformin clearance, resulting in increased plasma metformin levels, especially if metformin administration is continued [27]. The effect of metformin on plasma lactate concentrations in bariatric surgery patients has not been examined, but these individuals may be at higher risk for MALA due to increased metformin absorption and bioavailability [39]. Metformin plasma concentrations are approximately 2–4 fold higher in patients with type 2 diabetes and moderate to severe renal impairment (i.e., eGFR of 30 to < 60 mL/min/ 1.73 m2 or < 30 mL/min/1.73 m2, respectively) compared to healthy subjects [6,29]. Patients with type 2 diabetes are also at greater risk for hyperlactatemia, which is attributed to alterations in the redox potential [40]. As a consequence, patients with diabetes, especially those treated with 22 M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 65 ( 20 1 6 ) 2 0–29 metformin, have a reduced threshold for the development of lactic acidosis in response to a secondary event [19,25,26,41]. This scenario is consistent with individual patient case reports [42,43]. While some publications report a lack of association between plasma metformin concentrations and prognosis in MALA [44–46] and metformin levels in patients with MALA [45], these findings likely reflect the multiple different clinical conditions associated with lactic acidosis and varying degree of certainty in the timing of collection of key data such as plasma lactate and metformin concentrations proximal to the event [47]. Renal dialysis to remove metformin (and correct metabolic acidosis) has been recommended to treat MALA [34,35,48,49], arguing in favor of a relationship between elevated plasma metformin and increased plasma lactate levels. Although individuals can develop lactic acidosis for other reasons, in the case of MALA, metformin exposure appears to be the main risk factor. This is consistent with the observation in several publications [46,50,51] that patients with lactic acidosis who are taking metformin often have better outcomes than those who are not, suggesting that less severe secondary events may be sufficient to result in lactic acidosis in the presence of metformin. One possibility is that metformin limits a patient’s capacity to accommodate further increases in lactate induced by such secondary intercurrent events that ultimately trigger an event of MALA. 4.1. History of Metformin Labeling Regarding Patients with Impaired Renal Function The specific criteria put forth in metformin labeling (serum creatinine levels ?1.5 mg/dL [males], ?1.4 mg/dL [females] or abnormal creatinine clearance) to contraindicate metformin use correspond roughly to an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 [6]. A creatinine clearance of 60 mL/min/1.73 m2 is at the threshold of meeting the National Kidney Foundation’s definition of chronic kidney disease, stated as “either kidney damage or GFR < 60 mL/min/ 1.73 m2 for 3 months.” This level falls between Stage 2 (kidney damage with mild decreased GFR) and Stage 3 (moderate decreased GFR). The specified serum creatinine levels in the metformin label reflect a then practical but imprecise estimate of GFR because calculation of GFR from serum creatinine levels by the Cockcroft–Gault, MDRD equation and similar approaches is highly dependent on age, sex, and body weight [52]. As an illustration from the National Kidney Foundation (Frequently Asked Questions about GFR Estimates), a serum creatinine of 1.2 mg/dL in a 22-year-old Black man, a 58-yearold white man, and an 80-year-old white woman result in calculated GFRs of 98, 66, and 46 mL/min/1.73 m2, respectively. These values correspond to renal function categories of Stage 1, 2, and 3, respectively for those individuals. Although not documented in detail in the FDA’s Summary Basis of Approval for Glucophage, the appropriateness of these criteria was the subject of considerable discussion by both internal Agency staff and outside subject matter experts. Because of the concern about potential for MALA and the dependence on renal function for drug elimination, reviewers concluded that a conservative approach was warranted for metformin use in patients with renal insufficiency. Reviewers decided that any degree of renal insufficiency as reflected by the very rough proxy of serum creatinine should be contraindicated. The commonly listed upper limits of normal serum creatinine levels for men and women were used to define the contraindication with the understanding that these creatinine levels in some patients could reflect more than borderline renal dysfunction. The contraindication thresholds limit metformin use to patients who could be treated without having metformin plasma concentrations significantly exceed the ‘typical’ therapeutic range of Purchase answer to see full attachment