Rant: Bigger is not always better, Part 2

Part 2

Using the data from  Effect of Dose Size on the Pharmacokinetics of Oral Hydrocortisone Suspension by Toothtaker, Craig and Welling.  I've decided to change my hydrocortisone dosing a bit.  I'm reporting on it here so you all know how it goes.  Perhaps theory does not align with practice?

According to Effect of Dose Size, there is a "...nonporportional relationship between circulating hydrocortisone levels and the size of the oral dose."  5 mg of hydrocortisone yields 3.55 mg of cortisol.  10 mg of hydrocortisone yields 5.7 mg of cortisol.  If you'd like to see Part 1 of this post, click here.  

Here's how I'm figuring out my new dosing schedule.  Please do not change your hydrocortisone dosing without first consulting your physician.

1)  2/3 of the daily dose should be before noon based on a 7 AM wake up

2)   I wake up at 5 AM so "noon" is 10 AM for me

3)  1/3 of the daily dose should be after noon and before 4 or 5 PM

4)  Based on a 5 AM wake up, "noon" of 10 AM, 1/3 of my daily dose should be between 10 AM and 2 or 3 PM

5)  I take 45 mg of hydrocortisone per day split 10/10/10/10/5 according to the Effect of Dose Size the yield of my dosing is 26.35 mg [(5.7*4) + 3.55]

6)  To maintain the approximate yield of 26.35 mg per day while lowering the actual oral dosing, I'm going to take 40 mg split in two 10 mg doses and four 5 mg doses for a yield of 25.6 mg cortisol [(5.77*2)+(3.55*4)].  I will be cutting my overall hydrocortisone dose by about 1 mg HC.

7) Schedule will be as follows:

5 AM 10 mg HC

7 AM 5 mg HC

9 AM 10 mg HC

11 AM 5 mg HC

1 PM 5 mg HC 

3 PM 5 mg HC

8)  Next steps for me.  Set phone alarms and label accordingly.  Refill pill containers.

Although the yield for 5 mg doses is higher than for 10 mg doses, I chose to add two 10 mg HC doses because I'm too lazy to take pills 10 or 11 times a day (this includes vitamins and thyroid meds at night) and I only have ten alarms on my phone.  

I will try to post periodically about how this experiment works out.

Rant: Bigger is not always better

Get your mind out of the gutter!  I'm talking about hydrocortisone dosing.

I have hundreds of papers saved, all of which I've thought important at one time or another, most of which I have not read in their entirety.  I came across Effect of Dose Size on the Pharmacokinetics of Oral Hydrocortisone Suspension by Toothtaker, Craig and Welling.  

This is a highly technical study.  I will summarize the high points as I understand them.  Please pull this study and have a read!  Above, I've included a link to the abstract.  

I tend to have a lot of criticisms of studies but this one seemed pretty straight forward.  I'm sure someone with more knowledge of pharmacology could tear this apart.  Read on for my interpretation and quotes from the study.

1. "The elimination half-life was affected by dose size,..."
1. 5 mg 1.2 hours (72 minutes)
2. 10 mg 1.3 hours (78 minutes)
3. 20 mg 1.5 hours (90 minutes)
2. "The drug is absorbed rapidly into the circulation, achieving peak plasma concentrations within 1 hour."
3. "An overall five-fold increase in the tablet dose (10-50 mg) resulted in a 2.1 fold increase in mean C max [peak plasma concentration]..."
4. "A number of explanations was originally proposed to account for the nonporportional relationship between circulating hydrocortisone levels and the size of the oral dose."  The researchers eliminated several reasons and came up with "An increased free fraction during first-pass is likely to permit greater hepatic clearance, and to decrease the systemic availability of unchanged drug."  My interpretation:  your liver can only process so much hydrocortisone at one time.
5. "...the systemic availability of hydrocortisone is..."
1. 5 mg dose 71%  
2. 10 mg dose 57%
3. 20 mg  dose 56%
4. 30 mg  dose 40%
5. 50 mg  dose  40%
6. MY INTERPRETATION
1. You take a 5 mg dose and get 3.55 mg of cortisol out of it*
2. You take a 10 mg dose and get 5.7 mg of cortisol out of it*
3. You take a 20 mg dose and get 11.2 mg of cortisol out of it*
4. You take a 30 mg dose and get 12 mg of cortisol out of it*
5. You take a 50 mg dose and get 20 mg of cortisol out of it*

What can we, people on hydrocortisone, take away from this?  Bigger is not better.  Taking a 50 mg dose of hydrocortisone will NOT give you ten times more cortisol circulating in your blood.  Take smaller doses, more often to get the most out of your hydrocortisone dosing. 

Does your doctor have you on 30 mg of hydrocortisone/day all at once?  If so, you're not getting as much cortisol out of your dose as you could!  According to this study, you're getting about 12 mg of cortisol in your blood all at once instead of spread out through out the day.

In a more efficient scenario of 30 mg of hydrocortisone per day dosed 10/5/5/5/5 you'd be getting 19.9 mg of cortisol in your blood.  HUGE difference!

Many doctors subscribe to "less HC is better" and put patients on stupid, low doses which keep the patients from having any quality of life.  Physicians pay little mind to the pharmokinetics of hydrocortisone.  I can't blame them, it's a pretty obscure bit of science for an obscure disease.   Endogenously produced cortisol is about 10 - 15 mg per day (depending upon the source of reference).  If a doctor is fixated on these numbers and wants you to take an equivalent amount of oral hydrocortisone to the endogenously produced amount, you are screwed.  However, if you are taking 20 mg of oral hydrocortisone in doses of 10/5/5, you are coming in right in the ballpark at 12.87 mg of cortisol available in your blood!  Take 20 mg all at once and you get less, 11.2 mg of cortisol available in the blood.

Once again, physiologic dosing of hydrocortisone is best.  Smaller doses are more efficiently processed by the liver.  Smaller doses don't last as long (5 mg=72 minutes vs 10 mg=78 minutes) but if you are taking smaller doses more often, you won't feel ups and downs.  

How can this information be helpful in other ways?  Perhaps tapering hydrocortisone doses after an illness can be managed by talking smaller doses more often and less cortisol during each day of the taper?  If you don't feel great on the dose of hydrocortisone you're on, there is the possibility that changing the SIZE of your doses could help you feel better.  Taking smaller doses of hydrocortisone more often will provide you with smoother and greater hydrocortisone coverage (better blood sugar, blood pressure and energy).  If you're hyperpigmented and take large doses of HC throughout the day, hmmmmm, maybe that's your problem.  Very little cortisol is in your blood (less than your doctor thinks!) and it's triggering your pituitary to make lots of ACTH which will cause you to be hyperpigmented.  

Bigger is NOT always better!

*under ideal circumstances, your small intestine (where hydrocortisone is absorbed when you take it orally) health may vary

Rant: Let's start a revolution. Don't allow cortisol and ACTH testing to determine your hydrocortisone dosing.

"Treatment surveillance of chronic glucocorticoid

replacement is mainly based on clinical grounds because

no objective assessment has proven to be reliable for

monitoring replacement quality."

"Thus, in the absence of objective variables to measure

replacement quality, the doctor has to rely primarily on

clinical judgment, taking into account signs and

symptoms potentially suggestive of glucocorticoid overreplacement

or under-replacement (table). Underreplacement

bears the risk of incipient crisis and severe impairment of wellbeing."

Adrenal Insufficiency Arlt and Allilio

"Individual dose adaptation and monitoring of glucocorticoid replacement remains challenging as cortisol production is highly variable during the day and further influenced by many factors that activate stress responses like physical activity, pain, infections, psychological stress, low blood glucose, etc. Recommended daily hydrocortisone doses in primary adrenal insufficiency (PAI) are lower than estimated before ranging between 10 and 20 mg.  However, this reflects a mean need during the day and may not cover the need induced by additional stressors. Therefore, patients need to learn how to adapt their dose according to daily needs in a more flexible manner. Furthermore, comedication has to be taken into account...Some authors recommend weight-adjusted hydrocortisone dosing, thrice daily before food, leading to a reduction of intervals with excess cortisol exposure during the day and to reduced interindividual variability of cortisol profiles. This might be helpful when newly starting hydrocortisone replacement. However, other authors showed that there was no correlation of a clinical score assessing quality of replacement therapy with total or body weight-adjusted glucocorticoid dose. This demonstrates that dose finding has to be individually adapted and also requires patient education enabling the patient to correctly and autonomously adapt the hydrocortisone dose. Because of the nonphysiological cortisol profiles achieved by current replacement regimes, to date no reliable laboratory parameter exists for correct assessment of replacement quality. Even the serum cortisol day curves suggested by some authors only give a rough estimate and help to identify largely over- or underreplaced patients but are of limited value in the standard monitoring of glucocorticoid replacement. ^[4] Treatment surveillance is mainly guided by clinical judgment assessing daily performance, subjective health status and signs and symptoms of glucocorticoid over-replacement (weight gain, skin alterations) or under-replacement (fatigue, nausea, myalgia and joint stiffness). Fatigue is, however, a common complaint also under apparently optimized standard replacement conditions. Therefore, an increase in hydrocortisone should timely be reevaluated to avoid overdosing."

What is the Best Long-Term Management Strategy f0r Patients With Primary Adrenal Insufficiency? 

Quinkler and Hahner

More references for your reading pleasure:

Debono, M., Ross, R.J. & Newell-Price, J. (2009) Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy. European Journal of Endocrinology, 160, 719– 729.

Mah, P.M., Jenkins, R.C., Rostami-Hodjegan, A. et al. (2004) Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. ClinicalEndocrinology (Oxford), 61, 367–375

Arlt, W., Rosenthal, C., Hahner, S. et al. (2006) Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements. Clinical Endocrinology(Oxford), 64, 384–389.

So your question is, why does my doctor test my ACTH and cortisol?  The answer is simple.  He does no research and has even less comprehension of adrenal insufficiency than you know.

Testing ACTH is expensive and a waste of your blood and time once you've been diagnosed*.  Study after study concludes, "

*There are exceptions to this statement.  If you are secondary, ACTH may need to be tested.  If you are Cushing's and have had a BLA.  If you are primary and hyperpigmented, you may need your ACTH tested.  More than likely, if you're hyperpigmented and primary, you need more HC.

"ACTH cannot be used as

a criterion for glucocorticoid dose adjustment, since in

primary adrenal insufficiency it is invariably high before

the morning dose and rapidly declines with increasing

cortisol concentrations after glucocorticoid ingestion.122,124

Aiming at morning ACTH values continuously within the

normal range would, therefore, lead to chronic overreplacement.

However, in case of reappearance of skin

hyperpigmentation in primary adrenal insufficiency,

concentrations of plasma ACTH should be measured."

 Adrenal Insufficiency Arlt and Allilio

I really have no clue what you can do if your doctor recommends testing cortisol and ACTH except a) refuse b) just don't get the draw c) ask what he's basing his potential conclusions on (yes, easier said than done).  

The most important thing you can do is respect yourself.  Are you still suffering from symptoms of untreated adrenal insufficiency such as nausea, vomiting, diarrhea, fatigue, hyperpigmentation, low blood pressure?  Do you suffer from symptoms of Cushing's like weight gain, insomnia, easy to anger, purple striae, easy bruising and thin skin?  Let your symptoms guide you and your physician.  

Feel like crap and think you're on the "right" dose of HC?

1. Are you dosing your HC physiologically?
2. Does the amount of florinef you take keep your sodium consistently at 140 at 8 am, fasting after 24 hours on a normal sodium diet (2,300 mg)?
3. Is your free T4 1.3 if you're female and 1.4 if you're male?  GET YOUR RESULTS.  NORMAL is not an acceptable answer here.
4. Are you allowed to replace the hormones in which you're deficient like DHEA-S, testosterone, progesterone?

If you feel like crap and the answers to each and every question above is "yes", you need further testing and/or dosing assistance.  Get help.  If the answer is "no" to even one of these questions, work on each one in order with your physician.

In summary, doctors are wasting our blood, our money and our lives by testing cortisol and HC to determine the proper dosing since there are NO standards upon which to base their opinions EXCEPT clinical grounds!  

Let's start a revolution.  

Require your doctor to provide you with proof of why he wants to test your cortisol and/or ACTH to determine your hydrocortisone dosing.  He might fire you but it might be worth it.  You'll find someone who thinks you and your judgement is valuable.  Who knows?  You might feel better if you were allowed to trust yourself and your symptoms that YOU live with 24 hours a day, 7 days a week.