Jon,

Good point.  There are obvious differences between Cmax, the maximum serum concentration after dose, the average serum concentration, and the serum concentration of maximum therapeutic effect.  Tmax, the time interval at which Cmax occurs is another important pharmacokinetic parameter we need to know and understand in preventing CH with verapamil. 

In my opinion, all of us need to understand the pharmacokinetics and pharmacodynamics of any pharmaceutical like verapamil or neutraceutical like vitamin D3 we take.

If you look at my original post on this topic, I was careful to say "serum concentration" and not serum concentration of maximum therapeutic effect.  The two can be the same if the average serum concentration is higher than the threshold for a therapeutic effect.

The following two graphs illustrate what I'm talking about.  The first graph illustrates plots of verapamil's serum concentration over time from dose for sublingual and oral administrations.

Multimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or

As you can see the shape of these two plots are very similar.  You can also see that the sublingual verapamil plot reaches a higher Cmax at 55 ng/mL 1 hour after dose, where the oral verapamil reaches a lower Cmax at 45 ng/mL 1.5 hours after dose.

The second graph illustrates one measure of  verapamil's therapeutic effect, measured in PR interval.  Please note that this is not the therapeutic effect that prevents CH.  It's just an example.

Multimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or

In electrocardiography, the PR interval is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization); it is normally between 120 and 200ms in duration.  See graphic below:

Multimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or

In this case, verapamil increases the PR interval which slows the heart's pulse rate and this lowers the blood pressure, one of verapamil's therapeutic effects.

The actual mechanism of action of verapamil in preventing CH remains unknown, but likely deals with its capacity as a calcium channel blocker which causes the smooth muscles lining arteries and capillaries to relax. This helps stop or slow the rapid vasodilation associated with the pain phase of CH.

As illustrated above, it takes it takes roughly an hour and a half for verapamil to reach peak plasma concentration after oral administration. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating activity of the parent drug).

So, after this long-winded epistle, the simple answer to your question is there's a dose response relationship for verapamil in preventing CH.  As there are considerable variations between CH'ers in terms of preventative response at any given dose of verapamil, it's always best to titrate up in dose to find the lowest effective dose of verapamil in preventing CH.

Your practice of taking verapamil in the evening as it results in the best CH preventative effect is sound... and supported by plots of serum Cmax and Tmax for verapamil illustrated in the first graphic.

Now for the rest of the story as Paul Harvey used to say...  Verapamil, even at relatively low doses (120 mg/day), results in arrhythmia in roughly 20% of the CH'ers who take it to prevent CH.  That makes having an EKG prior to starting verapamil to establish a baseline and periodic EKGs (3 month intervals) during the first year of use a very good idea...

Please understand...  I'm not a doctor or a nutritionist...  I'm just a cranky 71 year old fighter pilot with a bee in his bonnet trying to introduce CH'ers to an effective, lasting and healthy method of preventing their CH... 

In order to do this with any credibility, I've gone back to school (make that home schooling) over the last five years, to learn how and why vitamin D3 is so effective in preventing CH.  The pharmacokinetics and pharmacodynamics of vitamin D3 (and other pharmaceuticals used to prevent CH) were two of the courses...

I'll leave you with a parting thought... 

In the history of modern medicine, medical scientists have yet to discover a medical condition caused by the lack of a pharmaceutical agent that wasn't already found naturally in the human body...

Take care and please keep us posted.

V/R, Batch

Hey Andy,

Good question.  I doubt there's an answer backed by irrefutable medical evidence as to the benefits of taking a probiotic while taking an antibiotic, let alone the effect of dose escalation.

In my experience and that of some real experts on maintaining a happy gut, i.e., a healthy microbiome of symbiotic colonies of  biota in the GI tract, maintaining this GI tract ecosystem is a basic step in maintaining good health... even while taking an antibiotic... 

Moreover, the evidence is building even among researchers reporting in neurological journals like Neurology, that maintaining a healthy microbiome has positive implications in several autoimmune disorders.

Sooo... with the above as an a backdrop, I'm inclined to think more is better.  I take Nature's Bounty Advanced Probiotic 10 with 20 billion live probiotic cultures in two capsules. 

So far, no problems... and I've taken this probiotic while dosing on PenVK at high doses in advance of, and following oral surgery for removal of a smart tooth that had been with me for over 60 years...

I also bumped my vitamin D3 intake to 50,000 IU/day following the oral surgery for a week as there was evidence of a root infection. 

The reason for the loading dose of vitamin D3 is simple... Infections trigger an immune response that sucks up vitamin D3 and it's metabolites like there was no tomorrow... and this creates a competition that can leave insufficient levels of vitamin D3 to prevent CH.

Go for it... and please keep us posted.

Take care,

V/R, Batch

Joshua,

Yuppers...  Your 25(OH)D is still too low at 62 ng/mL for a lasting pain free response to this regimen...  Did they measure your PTH?  Are you taking all the co-factors at the suggested doses? 

Howz the head?  If you're still on a pred taper and obtaining oxygen, it would appear the beast is still making house calls. If I'm correct, has there been any change in the frequency of your CH since starting this regimen?

Have you tried taking Benadryl (Diphenhydramine)?  An allergic reaction causes a flood of histamine that makes nearly all forms of CH intervention less effective... if effective at all.  Diphenhydramine is a first generation antihistamine that crosses the blood brain barrier to block H1 histamine receptors on neurons throughout the brain.  Second- and third-generation antihistamines cannot do this so will not be effective for CHers taking the anti-inflammatory regimen.

When the big pollen fall started last March and the CH beast started jumping ugly, I loaded at 50,000 IU for nearly a week then decided it was time to treat the allergy that was obvious from the first day...   I took 25 mg of Diphenhydramine every 12 hours and was again pain free by the second day.

Take care and please keep us posted.

V/R, Batch

Hey Joshua,

If I need to drive, I take the Benadryl (Diphenhydramine) in the late afternoon or evening when I'm done driving for the day.

There are a lot of factors affecting the 25(OH)D response to dose of vitamin D3 including variability between individuals.  Weigh and BMI are the primary factors, but any inflammation or an immune system response can both gobble up serum vitamin D3 and 25(OH)D at high rates.

It appears you're on the right path so it may be just a matter of time before you experience a complete cessation of CH symptoms.

Take care and please keep us posted.

V/R, Batch

Joshua,

A pain free day is a good sign of things to come... I like seeing comments like this.

Take care,

V/R, Batch

Hey Joshua,

Data from the online survey of CHers taking the anti-inflammatory regimen to prevent their CH indicate 10% will experience an initial 3 to 5 days of pain free response followed by a recurrence of CH symptoms.  However, with continued use, these CH symptoms dissipate and the CHer is again pain free.

I'm not sure why this happens, but suspect it has to do with the production of enzymes within brain cells needed to hydroxylate vitamin D3 to 25(OH)D and on to 1,25(OH)2D3, (calcitriol), the active hormonal metabolite of vitamin D3.  Once this enzyme production stabilizes, brain cells are able to hydroxylate sufficient calcitriol to maintain the genetic expression that prevents CH.

Regarding Chlorpromazine (Thorazine)...  I'd be very cautious.  It acts on so many neurogenic receptors with so many different adverse side effects, it is often referred to as a "dirty drug". 

It's also the drug you see administered to psychiatric patients who become agitated or combative to "Knock them out."  If you watched the movie One Flew Over the Cuckoo's Nest or Terminator 2: Judgment Day you saw it administered.

Take care and please keep us posted.

V/R, Batch