Wednesday, November 27, 2013

Obese patients and emergency contraception

In a story featured on NPR yesterday, news of additional warning information on labeling for oral emergnecy contraception in Europe has raised questions as to why similar label changes have not yet occured in the USA. The story focuses on a recent meta-analysis [1] that describes the effectiveness of the oral emergency contraceptives levonorgestrel (Plan B) and ulipristal acetate (Ella). In this case, I must agree with the FDA, that there is not enough data to make a change in the labeling, and further analysis needs to take place.

The meta-analysis was comprised of 2 studies randomizing patients to either agent 72 hours and 120 hours (levornorgestrel significantly looses efficacy after 96 hours) after unprotected intercouse, respectively. In each study, only patients who followed up were included. In total, of the 3445 patients included, there were 60 pregnancies, of which, 38 occured in patients who recieved levonorgestrel and 22 who recieved ulipristal. Despite this small number of pregnancies, a large amount of analysis was conducted. In short, while ulipristal was associated with a significantly reduced risk of pregnancy, both agents were associated with a reduced efficacy at higher BMIs (>30)- levornorgestrel had the greates loss of effectiveness. But again, the numbers were quite small; 6 pregnancies of 227 patients with BMI >30 who were randomized to ulipristal and 14 of 242 with BMI >30 randomized to levonorgestrel. Converting BMI to weight, levonorgestrel appeared to be less effective in patients who weighed >70 kg, and ulipristal loosing effectiveness in patients weighing >88kg. When reviewing each study individually,[2,3] ulipristal was non-inferior to levonorgestrel, and there were no investigations into the effect of of BMI or weight. However, upon each meta-analysis conducted, ulipristal was consistently shown to be superior. Before too much skeptecism creeps in, and investigation into the funding sources of these studies (when they're even disclosed), it is worth investigating the pharmacokinetic theory that may exist.

In obese patients, there are a number of assumptions regarding what pharmacokinetic and pharmacodynamic changes occur. The only agreement is that changes do occur. Most of the data we use to dose medications in obese patients are either 1) computer modeled over-simplifications with assumed variables or 2) based on social definitions (like ideal body weight) that were never intended to be used for medication dosing purposes. But, in general, it is assumed that a lipophilic drug with a large volume of distribution (for example; levonorgestre; Vd of 1.8 L/kg) would be predicted to have lower plasma concentrations due to higher volume of adipose tissue, thustly, lower efficacy. However, the PK data with levonorgestrel demonstrates that there is no change in Vd in obese patients, but rather, an increase in AUC (total exposure), longer half-life, longer time to steady state and decreased hypothalamic-pituitary-ovarian inhibition.[4]

Despite these observations, according to the latest Cochrane analysis, there is no change in effectiveness of OC with increasing BMI.[5] Important to note, however, is that these studies are analyzing long term OC use- not emergency OC.

Extrapolating the PK data to emergency OC use, one could theorize that with a larger AUC, and longer time to steady-state, a one time dose may loose effectiveness. What is equally unclear is the impact of increasing the dose. It is clear that the effect of decreased effectiveness is not exclusive to ulipristal,[6] and should not be considered an alternative in obese patients (as described in the NPR piece), copper IUDs would be considered as an alternative.

1] Glasier A, et al. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception 84 (2011) 363–367
2] Creinin MD, Schlaff W, Archer DF, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol 2006;108:1089–97
3] Glasier A, Cameron ST, Fine PM, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized noninferiority trial and meta-analysis. Lancet 2010;375:555–62 
4]Edelman A, Carlson N, Cherala G, et al. Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity. Contraception. 2009 August; 80(2): 119–127
5]Lopez LM, Grimes DA, Chen M, et al. Hormonal contraceptives for contraception in overweight or obese women. Cochrane Database Syst Rev. 2013 Apr 30;4:CD008452. doi: 10.1002/14651858
6]Moreau C, Trussell J.Results from pooled Phase III studies of ulipristal acetate for emergency contraception. Contraception 86 (2012) 673–680

Friday, November 22, 2013

Carboetomidate: The Answer to the Prayers of the Intubated Septic Patient?

With all the controversy surrounding the questionable association of mortality associated with the use of etomidate for the purposes of induction in the septic patient, it only seems reasonable to recommend alternative agents in this setting...or design therapeutic analogues.

Enter carboetomidate.

Carboetomidate is a derivative of etomidate that contains a pyrrole ring in its structure, as opposed to an imidazole ring that is found in etomidate.

What is the significance of this? It has been proposed that drugs that contain an imidazole ring within its chemical structure, such as etomidate, have the effect of suppressing the synthesis of adrenocortical steroids. For etomidate, this is thought to be secondary to its inhibition of the enzyme 11-β hydroyxlase. This has been shown to occur through the interaction of the nitrogen atom in the imidazole ring with the active binding site of this enzyme. With substitution of the nitrogen atom for a carbon atom, it has been hypothesized that the interaction with the enzyme will not be as strong, leading to reduced inhibition of cortisol synthesis.

A few animal studies (1, 2)  have been conducted evaluating this effect to determine the potential clinical impact. These studies have shown that even with a minimal change in the structure, hemodynamic stability and sedation was maintained with effects demonstrated to be similar to etomidate in terms of duration and potency This was demonstrated to occur due to modulation of the GABA receptor by carboetomidate. However, the onset of action of carboetomidate was shown to be a bit slower than etomidate in one animal study (4.5 ± 0.6 s with etomidate versus 33 ± 22 s with carboetomidate) (3), which may be less than desirable in the setting of rapid sequence intubation; human studies have yet to be conducted to determine if this is truly the case.

It will be interesting to see this unfold and the niche that carboetomidate will potentially have should it be approved for use as an induction agent in humans.

  1. Pejo E, Feng Y, Chao W, et al. Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia. Crit Care Med 2012; 40:187-192.
  2. Shanmugasundararaj S, Zhou X, Neunzig J, et al. Carboetomidate: an analog of etomidate that interacts weakly with 11-β hydroyxlase. Anesth Analg 2013; 116:1249-1256.
  3. Cotton JF, Forman SA, Laha JK, et al. Carboetomidate: a pyrrole analog of etomidate designed to not suppress adrenocortical function. Anesthesiology 2010; 112:637-644.

Thursday, November 7, 2013

Flumazenil: Friend or Foe?

The first drug that I ever had clinical experience with was flumazenil.

It was as a student during my final year of pharmacy school, and it occurred while I was on my clinical practice rotations. We had a patient on our ward service who had an MRI and was extremely lethargic following the procedure. We soon discovered that our patient received more lorazepam than he could tolerate prior to the procedure, which seemed to be the only contribution to the current state that he was in. Otherwise, his vital signs were normal and he was in normal sinus rhythm on the EKG monitor. We had recommended the administration of flumazenil for our patient, and we were at the bedside as the physician was administering the agent. It worked after about one minute, at which the point the patient began to become aroused and much more oriented to his surroundings. At the time to me, it seemed to work like magic. As we discussed the case, the mantra that was driven into my head regarding flumazenil at that point was to be cautious of its use due to its potential in lowering the seizure threshold.

The evidence surrounding this touted risk of flumazenil originates from one of the earliest human studies evaluating the use of flumazenil in benzodiazepine overdose, where of the 326 patients enrolled in this double-blind, placebo-controlled trial, four patients experienced seizures and cardiac arrhythmias. The likelihood of these events were increased with the ingestion of tricyclic antidepressants and patients who were using benzodiazpines for seizure control. In addition, another study published during that same year analyzed 43 patients who seized subsequent to flumazenil administration, and precautionary measures were recommended regarding the use of flumazenil in patients who therapeutically use benzodiazepines for seizure control and those who were concomitantly on an exhaustive list of other medications that may increase the risk of seizures. In addition, several other studies do show an association with the administration of flumazenil and the incidence of seizures in patients with brain injury and ingestion of proconvulsive agents in the absence of benzodiazepines.

However, a number of studies have been published since then that calls into question the true incidence of seizures following flumazenil administration. In one study of 110 patients who received flumazenil for suspected benzodiazpine overdose, not only did it demonstrate the potential benefit of flumazenil unmasking the type of intoxication in those who responded to flumazenil than those who did not, but none of the patients experienced seizures or arrhythmias, even in those patients with multiple toxicity secondary to benzodiazpines and tricyclic antidepressants. One retrospective study did find that of 904 patients who received flumazenil, 13 patients experienced seizures following administration, with most of these patients having co-ingested proconvulsive agents. In addition, a retrospective study demonstrated that the administration of flumazenil was not associated with seizure activity in pediatric patients. 

The use of flumazenil may be warranted in a number of specific emergent situations, namely:
  1. Pediatric ingestions;
  2. Iatrogenic toxicity (as described in the case above); and
  3. For the purposes of reversing the effects of a paradoxical response associated with a pure benzodiazepine overdose. 
However, when it comes to the risk of seizures following the administration of flumazenil, I do not believe we can really appreciate the true incidence. The number of times that I have used flumazenil is less than a handful and was certainly warranted in all those situations for one of the three indications listed above. In all of those instances, none of my patients experienced seizure-like activity.

Some mantras in medicine and pharmacy should be appreciated for their face value at best.

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