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Pharmacokinetics is hard ! Differences between clonazepam pills and liquid/drops

K

Kdem

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I have experience with both clonazepam pills 2 mg and the liquid (drops) as made by the manufacturer (Roche). For years I have always taken tablets only. The idea is to taper the drug.

There is a tendency of the liquid to have a faster and stronger onset of action and it seems last shorter. In some ways, the liquid feels 'harsher'. I take either tablets or liquid once a day. (I always split the tablets in two or four pieces.)
However, the drops also seem to have a different effect than the pills ! It's hard to put into words, so it's probably best not to even try. But up to a point it feels a bit like a different drug. And this drug is hard to tolerate. I probably have a sensitized CNS and sensitivity to this drug.

The excipients in the tablets: lactose, pregelatinised starch, microcrystalline cellulose, magnesium stearate.
The drops/liquid: sodium saccharin, peach flavor 85502, glacial acetic acid (E1520), brilliant blue FCF.
I take both tablets and drops with some water.

According to Roche the onset of action of the drops is slightly faster, but that is all the information they have. It's an old drug.

My impression is the the distribution of the active substance (clonazepam) in the body is affected. To what extent this is about distribution outside the CNS, to what extent this is about distribution into the CNS, I do not know.

Does anyone have a clue about why am experiencing such different effects between tablets and drops ? What could/would be going on ? The tablets are probably more 'gentle', but not ideal for tapering.
 
Usually it is just the dissolution of the tablet and perhaps slightly faster absorption that is the difference among different dosage forms however there are cases where bioavailability or the effects of stomach contents can have an effect depending on the form. I never have seen Klonopin liquid and just looked it up and found no info. Is it possible it is Ativan or Diazepam in the liquid?
 
It is clonazepam. Specifically, the Rivotril brand (Roche). It is available in drops that contain 0.1 mg clonazepam.
Searching for Rivotril drops should yield results.

There is no diazepam, lorazepam or any other benzo in the liquid.

It was a bit puzzling how to take the drops, but they can be dissolved in some water or taken directly from the spoon and swallowed with water.
 
^ it's 'Rivotril drops' by Roche

EDIT: ops, posted at same time... yeah, so it is clonazepam indeed. btw when you phrase it that way it looks like a perfume name.
 
It seems very easy to absorb benzo solutions sublingually and through buccal tissue. If you hold the solution in your mouth for any length of time the effects come on much faster then they would orally. I agree with you in that I found the subjective effects of oral vs buccal/sublingual clonzepam quite different in essentially all of the aspects you mentioned.

To get around this you may try using a pipette to squirt the solution as far back in your mouth as possible and swallowing it immediately.
 
Ah, I see. I am in the US and we do not have that here. I took a quick look at the medication info sheet and it makes no mention of any huge change in the kinetics. Once it gets into the circulation, nothing should be different between the two normally but I will see if there is anything else I can find.
 
Once effect that I do feel is that slightly difference in the liquid form. A little bit weaker than the equivalent dosage in a pill form, IMO/E.
 
pr0d1gy said:
It seems very easy to absorb benzo solutions sublingually and through buccal tissue. If you hold the solution in your mouth for any length of time the effects come on much faster then they would orally. I agree with you in that I found the subjective effects of oral vs buccal/sublingual clonzepam quite different in essentially all of the aspects you mentioned.

To get around this you may try using a pipette to squirt the solution as far back in your mouth as possible and swallowing it immediately.
Click to expand...

Generally, I let it dissolve in water. Then I stir it a bit and drink it. So, it should be equivalent to pill form.
I don't let it absorp in the mouth, except the little amount that cannot be avoided.
 
There is of course a difference between therapeutic use on the one hand and what you can get when you are physically dependent and have difficulty tolerating the drug on the other hand.

I did post the excipients, I am not sure what else I can add add about the respective dosages.
Except that I do notice if I swallow the pill whole or I break it into quarters.
 
Could stomach PH possibly play a role ? (difference tabs vs drops)

'Antiepileptic Drugs', René H. Levy, (google books), page 190, 'absorption': 'The rate and extent of absorption of clonazepam were decreased in patients with a higher than normal gastric PH' ... 'compared with absorption in patients with a normal gastric PH who were treated with caffeine'.

'microcrystalline cellulose' Perhaps this excipient is related to delayed absorption ? It's a bit complicated for me.
 
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There should be no major difference in bioavailibility or dose strength... clonazepam is quite fat soluble and will take about the same mount of time to migrate from the stomach to the brain in either case.

and a lactose/cellulose tablet will disintegrate quite fast in the gut btw.

Lactose is the water soluble binder that dissolves to disintegrate the pill.
Microcrystalline cellulose is basically tree pulp used as filler to bulk the pill out.
Pregelatinized starch is water soluble starch as a filler. It will swell when wet and disintegrate the pill.
Magnesium stearate is a waxy coating to help release the pills from the molds.

On paper there should be no difference between drops and oral. Unless you are measuring the liquid incorrectly?

Clonazepam will be very stable at room temp in solution or pills btw.
 
Then I am at a loss.

'microcrystalline cellulose' is the only major difference if you compare the 2 mg and 0.5 mg tablets.
I know for certain that the tablets are absorpbed slower. Is there a difference in 'distribution' ? I suspect there is.
The drops certainly have a different effect.

Regarding the 'quite fat soluble': I have read different 'opinions' about that. Varying from low/intermediate to high.

I know it is supposed to be very 'hydrophobic'. I'm just not sure if that plays a role.

In a way, the drops feel more like a quick 'hit' while the tabs have a slower and more gradual onset.
I am hypersensitive to this drug.

As I understand, there is no first pass effect ?
 
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I would speculate that with the clonazepam solution (liquid drops) you have a lot higher probability of it being absorbed in the mouth, and at such pH it should mainly be in the closed-ring form, which is absorbed a lot better than the open-ring form. How much liquid do you take per dose? I assume it's a pretty concentrated solution, which would also rather increase the fast absorption in the mouth. Clonazepam from the pills can hardly be absorbed in the mouth (requires the disintegration of the pill), and since that mainly starts in the stomach, where the pH is quite low, it is only absorbed in the open-ring form (it tends to be in the open-ring form at low pH); which makes absorption slower until it reaches the intestines where I imagine it would go back to the closed-ring form.
 
Open ring versus closed ring ? I do not understand. Can you explain that 'ring' issue ?

20 drops in a dose, that equals 2 mg. Very little of that is absorbed in the mouth since I dissolve it in water, drink the water, followed by more water. In total not more than a full glass.
 
Benzos can be in two different forms: with an open or a closed ring (in their molecular structure). At low pH, one of the rings in the molecule tends to reversibly open and the molecule becomes considerably more polar (due to the positive charge), so its absorption rate is reduced. For example, ring opening of midazolam:
ea82ae2a3b.jpg


Well, that's just one possible way to explain it. I really can't see any other reason the two (liquid vs pill) should have different kinetics.
 
Thanks, that may explain some things.

In liquid form the substance is obviously disintegrated and as such it should be absorbed much faster. I think that it enters the bloodstream fast in that state. Different sources give different rates for the absorption of tablets. Up to 4 hours in some people.
Conceivably, the distribution of the drug in the body could be different ? Officially, it's not an 'extended release' formulation.

Also, I think I'm chronically dehydrated by the drug. No dry mouth though, the drug tends to stimulate the production of saliva. Perhaps that does something too.

Would you say that the polarity of the drug (PH blood or whatever) affects binding to benzodiazepine receptors or entering the CNS ?
 
As soon as it enters the bloodstream, it goes back to the closed-ring form (blood has neutral pH) and from there on there is no difference between the two (liquid vs pill). So no, there should be no difference in distribution (as soon as it enters the bloodstream) and CNS effects on receptor level - except for the difference in blood concentration of course.

Honestly I can't see significant difference between liquid or pill form, so I think it may just be that you're somehow especially sensitive to slightly increased rate of the "come up". Does drinking more water help against feeling dehydrated?
 
Does drinking more water help ? Pretty much no matter what, I tend to lose water weight fast. I once tried diazepam, and on that drug I weigh a bit more !
I'm not sure about the mechanism. Evaporation through the skin ?
It may help a bit, but I lose it anyway.

An odd thing, sometimes it seems that after drinking water the clonazepam 'comes on' in the sense that I feel it having an effect. Don't ask me how. A bit like taking the drug. Change in blood PH ?? Absorption of a remnant from the intestines, from bile (a place that has a relatively high concentration), distribution from tissues into the blood/CNS ?
Once, after drinking little in the evening and morning - I felt some sedation after I drank two glasses of water at noon !

If I truly drink very little in the evening/night after taking the drug I can actually feel it after drinking some water ! Normally I don't do that though.
 
I'm trying to see if I can get a bit more information. I found this neat PDF file. it is not about the Rivotril drops per se, but clonazepam in tablets compared with clonazepam in liquid form.

https://celerion.com/wordpress/wp-c...versus-Tablet-in-Healthy-Adult-Volunteers.pdf

There is so little information available from Roche that I'm pretty much on my own. And of course, any help I can get here.

Sources generally indicate that the bioavailability is 90 %. Would it be correct to conclude from this chart that the bioavailability is higher (100 percent ? Cmax for liquid 14.1 vs. tablet 12.8 (14.1/12.8=about 1.1 higher Cmax).
Or does it indicate that the peak is simply faster and higher, thus the duration of action shorter ?
Or alternatively, that there is a difference in drug distribution in the body ?

Pharmacokinetics isn't exactly my expertise. Is anyone able to make out anything from the chart ? I for sure notice a difference.
 
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A higher cmax doesnt mean higher BA. Possibly it could be from incomplete dissolution of the solid tablet form but seems unlikely. There should be no difference in distribution between the two, as once either reaches the bloodstream, they basically are the same. If you are looking at Vd (volume of distribution) you need to realize this is simply a PK parameter, and doesnt reflect any actual physiological volume. High Vd drugs simply mean a drug isnt confined simply to the blood but widely spread through various tissues. So a Vd of around 3-8 means the drug is confined to the blood (usually polar drugs or ones highly protein bound) and a large to very large Vd means it can be found in many tissues. So if the tablets had say a Vd of 80 and the liquid 90, it has very little actual relevance other than you can say both are highly distributed to various tissue.
 
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