I have added in a few extra points in order to try and help support my case. Make sure you have read all of the first page (excluding the calculations). Again, I haven't really bothered referencing the majority of this, it is mostly from physiological or pharmacological theory. The references which I have used, stand the same as the first rebuttal.

However, using Goodman & Gilman's,The Pharmacological Basis of Theraputics,(9th edition) and Moffett, Moffet and Schauf, Human Physiology Foundations and Frontiers, Second Edition, will have most of the enclosed information. (Some of the first section may infact be biology references

Death - What happens?

Even though someone (falls into a coma) and is dead after 30 seconds, the cells of the epithelium and tissues may still be alive, at least enough to deacetylate any remaining heroin. This may be true, however the situation is certainly different to that of a living person after 10 minutes (when the volume of distribution has maximised). After a person "dies", and the blood flow stops, the normally balanced hydrostatic and osmotic pressures between the blood stream and the interstitial space is distrupted. The movement of water between the capillaries (the blood stream in this case) and the interstitial fluid is dependant on two factors: the first is the permeability of the capillary, the second is the net force of the hydrostatic and osmotic forces between the two fluids. When the blood flow stops, hydrostatic pressures increase, and thus the volume of blood decreases. The result is a higher drug plasma concentration than that at the time of death. As of this point in time, I have no confirmatory information regarding the permeability of blood vessels after death, so I cannot postulate how much heroin would continue to enter the tissues. Certainly, it could only leave the blood stream via passive diffusion, not by convectional methods in flowing blood. It would not suprise me however if (as the cells are now dying/dead) the permeability coefficient decreases, due to activation of clotting factors, or due to the dysfunction of the blood vessel epithelium (it is known that shock does result in a reduction of perforation of drugs(1)) or perhaps the osmolarity changes in this system (increased protein content in the interstitial space) which results in little movement of drug into the tissue. The end result is the drug will not move into the tissues to the same degree as a living person. The increase in blood concentration and the reduction in drug movement to the tissues would thus have a large impact on the volume of distribution, which was the major issue of this critique. To actually give a figure for this change is impossible with the information we have.

What about these new calculations then?

Unfortunately, to calculate the volume of distribution at any point in time during the distributive phase is impossible, or at least impossible to calculate with the information I have. I have given some reasons though of why the blood concentration may be higher than normal, but wouldn't this be the case in every death? Perhaps. As I have mentioned in my reply to Roger, there is a difference between Kurt's death and those of most drug overdoses, notably the higher blood concentration and the shotgun damage. Opiates induce respiratory depression, which may cause coma, but as opiates have relatively little effect on the cardiovascular system, the heart will continue to pump for a certain period of time after breathing stops (usually until it is starved of oxygen, which is around three to five minutes after respiration stops). By my reckoning, a gunshot would result in a much more rapid stoppage of the heart. It may be that the effects which stop a significant proportion of the drug movement begins much sooner, thus the volume of distribution of the final situation is lower than for 10 minutes after a dose in living people. The sooner someone's blood stops flowing after dying, the smaller the final volume of distribution will be. I confirmed with a pharmacologist today that it would definately be a lot different, but she also could not give me an exact figure to work out such a volume of distribution (Personal communication, Dr. Judith Walker, School of Physiology and Pharmacology, University of New South Wales).

There are still models you could generate to determine possible volume of distributions, but as of this point, I haven't eluded a definately accurate method of determination.. as you will see in the next section, you can still use the half-life of heroin to generate an approximate model of the situation after 30 seconds or so.

So was Kurt incapacitated virtually after 10 seconds or so?

All is not lost in calculating the effect of a dose of heroin after certain periods of time. This can be achieved due to the fact that there is little elimination of the drug by the kidneys (and the liver metabolism would count in the "tissues" side of the situation). If you assume all of the heroin will enter tissues from the blood stream and the half-life of the drug entering the tissues is 2.5 minutes (from my last calculations, we'll ignore the correct 3 minutes)... then.. you can generate a formula which will calculate the percentage of a dose in the tissues at any one time. Before I show this formula, I want to clarify why half-life is satisfactory to use in this situation. Half-lives are not useful when both the clearance of a drug and the volume of distribution changes. Half-lives are defined as:

t1/2 = (approx) 0.693 x Vss / CL. Where Vss is the volume of distribution at steady state (in this case, Vmax can be substituted for Vss, because we aren't considering the elimination phase of the morphine) and CL is the clearance of the drug.

In this situation, clearance is constant, because the rate of elimination is only dependent on the plasma concentration of the drug. (nothing is limiting the movement of heroin into the tissues.. although if the deacetylating enzyme was saturated, that would change things).

The relationship between the volume of distribution and the plasma concentration (as mentioned in my first rebuttal) is D = V x C (D = total dose, V= volume of distribution and C=plasma concentration).

As you can see, as concentration decreases, the volume of distribution increases (as the dose taken is constant). In fact, the volume of distribution moves inversely proportionally to the concentration of the drug in plasma. Keep this thought in mind.

Any year 12 chemist can do the next part... if you imagine the drug is moving from the blood to the tissues in a half-life fashion similar to the decay of a radioactive isotope.. you can calculate percentages of the drug which has moved (or not) by:



in this case.. k = 1 / 2.5 (to convert minutes into halflives)

Substituting t=0.5, k=0.4, you can see that the percentage of drug entered into the tissues is approximately 13%. *** Note: This is not even considering approximate "10 to 20 second" delay between injection and the beginning of its effects(2).

If a dose of 240mg of heroin was taken, this would translate to the equivalent to a dose of around 31mg of heroin in the tissues (and hence the equivalent effect thereof after 10 minutes).

If you are tolerant to that dose, then the effects of heroin at that point in time is relatively small. Granted, as time continues, 80mg and beyond will be reached, but if you are highly tolerant, then heroin's effects have not impacted (remember it's all about achieving the required ratio between receptor and drug for overdose). For a dose of 240mg, 80mg in the tissues (and so 2/3 of the drug is in the bloodstream) is theoretically 1.5 minutes (gotta love the power of log).

Of course, whether this theoretical value is applicable is another issue. But, even if we ignore all the possible reasons why the volume of distribution may not be maximum, using the half-life of heroin (which is conservatively simplified towards active metabolites side) a person may not suffer major overdose symptoms for up to 1.5 minutes. How about being incapacitated? Many of the typical symptoms in normal doses of opiates would also be the first signs of toxic effects, such as itching, nausea/emesis and later, sedation(1). The definition of a sedative drug is: drugs which decrease activity, moderated excitement, and calms the recipient(1). Even though a person may be sedated, that does not mean they are incapable of doing anything, rather it is more of a calmness rather than a paralysis. As the dose rises into the high toxic/lethal range, more toxic effects such as seizures and respiratory depression can occur (although seizures may only occur in doses above that required for anaesthesia for potent opiates)(1). If you examine the "toxic" ranges for high-tolerance people (ranging from 10 to 70mg), it is possible for people not to suffer toxic symptoms until their dose approaches 70mg, at least major toxic symptoms such as respiratory depression and pulmonary edema(1,2).


Comment on the "Heroin is very fast acting" section within Incapacitated or Dead Before Gunshot section

Well, I've managed to find reference number 75 in this paragraph.. and what Roger says compared to the entire quotation is interesting.. firstly, let me type out the whole quotation (in the 2nd Edition 1986 of this book by Platt):

"This rapid uptake of heroin by the brain itself was demostrated in a study of rats by Oldendorf, Hyman, Braun, and Oldendorf (1972) who compared the brain uptake of morphine, codeine, heroin, and methadone 15 seconds after injection into the carotid artery. This procedure bypassed the blood-brain barrier. They found the uptake of heroin to be 68%, when it was taken as a percentage of a previously injected reference substance as a baseline. In contrast, the uptake of methadone was 42%; codeine, 24%; and morphine, too small to be measured. Oldendorf et al conclude that "the high uptake of heroin... indicates that an abrupt entrance of heroin into the brain tissue probably occurs 10 to 20 seconds after the usual intravenous injection by addicts. "

Two things... firstly, they derive the value of 68% as a comparison of a "reference substance" but there is no indication of what that substance is. Certainly, more heroin enters the brain from the cerebral-spinal fluid compared to the other drugs in question, but this IS excluding the blood-brain barrier (which heroin again does pass more easily than the other drugs). Nothing is necessarily wrong with the information above, but certainly to claim that "It would be a mistake to think that even a severe addict could intravenously inject triple the maximum lethal dose of heroin and survive 10 to 20 seconds." due to the fact that "15 seconds, 68% uptake into brain with heroin" as used in the essay is a very bad assumption. Firstly he ignores to tell everyone that the heroin is initially in the cerebral-spinal fluid, and secondly, even worse, his essay implies that 68% of the heroin is in the brain after 10 to 20 seconds.. which is false. Hopefully that point is now clarified :)

Bradley Speers
bspeers@fl.net.au