DUID cases and the context of analytical chemistry results

On April 10, 2012, in Pharmacology, by Justin J. McShane

In a Dri­ving Under the Influ­ence of Drugs (DUID) case there are many ques­tions that the gov­ern­ment has to answer in order for there to be a con­vic­tion. One of the most impor­tant ques­tions that the gov­ern­ment likes to frame the case in is whether or not there is impair­ment? This is the incor­rect ques­tion, the prop­erly stated ques­tion is whether or not the gov­ern­ment can with the infor­ma­tion pro­vided and pre­sum­ing noth­ing can validly con­clude impair­ment for a spe­cific lim­ited pur­pose, mean­ing safely dri­ving an automobile?

Impair­ment is a tricky con­cept when it comes to drugs.

We have blogged before here on a six part post on Phar­ma­col­ogy. Our posts focued on the fol­low­ing top­ics:
Part 1. Intro­duc­tion
Part 2. Phar­ma­co­ki­net­ics
Part 3. Phar­ma­co­dy­nam­ics
Part 4. Bioavail­abilty
Part 5. “Free ver­sus Bound Drug“
Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

In a DUID case, the lab­o­ra­tory is asked to test the blood. The ques­tion is: “For what?” Whether it is GC-MS or LC-MS, there is no uni­ver­sal method that will detect and quan­tify for all drugs of abuse. The typ­i­cal work flow and method of analy­sis in a crime lab­o­ra­tory can be described thusly:

The approved meth­ods for analy­sis are one or more types of immunoas­say (IA) screens, con­firmed by gas chro­matog­ra­phy and mass spec­trom­e­try (GC/MS). These IA tests as screen­ing tests are designed to be qucik and easy to use pro­vid­ing for a high rate of false pos­i­tives and some false neg­a­tives. If you test below the drug cut­off lev­els on the ini­tial screens, the lab does not report it as pos­i­tive or con­tinue with the con­fir­ma­tory tests. This can be an issue in the case of a false neg­a­tive as we will dis­cus below. If you test above the cut­off on the ini­tial screens, but below them on the con­fir­ma­tory test, the lab may or may not still report it as pos­i­tive and quan­tify it.

Speak­ing from strictly a phar­ma­col­ogy point of view and not from a legal prob­a­ble cause to test/search point of view, it is best prac­tice to test for every­thing. The rea­son being that there may be drugs whose pres­ence in their free form may, in com­bi­na­tion with the detected ana­lyte, com­pete for cer­tain recep­tors and may com­pete for elim­i­na­tion. If you only look for one spe­cific drug and miss the other drug that may have an antag­o­nis­tic effect, then you may incor­rectly con­clude pos­si­ble impair­ment when in fact when glob­ally exam­ined with a broader scope search, there is no likely phar­ma­co­dy­namic effect or that not valid con­clu­sion can be drawn based upon the data and the lack of information.

This is some­thing that we should keep in mind when lit­i­gat­ing these cases. If the lab­o­ra­tory does a very lim­ited search using LC-MS or GC-MS using a par­tic­u­lar col­umn that only is use­ful for dis­cov­er­ing bar­bi­tu­rates, for exam­ple, then it will likely be no good at separating/detecting prop­erly and validly for drugs that have antag­o­nis­tic effects that may com­pete or super­sede the effects of the dis­cov­ered barbiturate.

This is a major prob­lem in mod­ern testing.

How can there be a valid call of pos­si­ble impair­ment if you haven’t elim­i­nated a poten­tial legit­i­mate source of non-impairment, namely a drug in a suf­fi­cient quan­tity that has an antag­o­nis­tic effect?

So, the ques­tion becomes what did they test for and did they test for drugs that pro­vide antag­o­nis­tic effects?

Only in the bizarre world of law can lack of test­ing for the antithe­sis prove the thesis.

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Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Why per se Driving Under the Influence of Drug Based Prosecution is Not Scientific and How Probation Violations for Marijuana Use May Be Wrong

On March 13, 2012, in Analysis, Chemistry, Equipment, Ethics, Identification, In The Courtroom, Laboratory Procedure, Pharmacology, by Justin J. McShane

I can­not imag­ine that a sin­gle ratio­nal and sane per­son cares for drug impaired dri­vers to be on the road among us dri­ving what amounts to a guided mis­sile weigh­ing about 3,000 to 5,500 pounds or more. As has been shown time and again, a drug intox­i­cated dri­ver can be a weapon of mass destruc­tion. The right­ful pros­e­cu­tion and appro­pri­ate pun­ish­ment of drug impaired dri­vers is a good thing.

What I sug­gest is not “good,” “just,” or even “fair” is the pros­e­cu­tion and dra­con­ian pun­ish­ment of non-impaired dri­vers as if they were dan­ger­ous drugged drivers.

What ratio­nal per­son can disagree?

Is this what is hap­pen­ing in the United States today? Yes

This ques­tion is one of the most beau­ti­fully artic­u­late and hor­ri­bly com­pli­cated issues pos­si­ble when it comes to mar­i­juana in particular.

We have blogged here before about the gen­eral notion of the per­ils of inter­pret­ing an ana­lyt­i­cal chem­istry result stand alone: “Phar­ma­col­ogy For Lawyers Part 6: Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result”

What makes mar­i­juana also par­tic­u­larly inter­est­ing is the well-known and well-studied (pri­mar­ily by Mar­i­lyn A. Huestis, Ph.D., Senior Inves­ti­ga­tor Chief, Chem­istry and Drug Metab­o­lism Sec­tion in the National Insti­tutes on Drug Abuse) counter clock­wise hys­tere­sis effect in terms of  the user’s own sub­jec­tive reported phar­ma­co­dy­namic prop­er­ties and drug con­cen­tra­tion. This is shown on the graph below.

counterclockwise hysteresis of marijuana
The coun­ter­clock­wise hys­tere­sis of mar­i­juana sub­jec­tive report­ing over the course of time ver­sus blood con­cen­tra­tion of tetrahy­dro­cannabi­nol (THC)

As one can clearly see from the graph above, and what is impor­tant about these hys­tere­sis curves is that if you look at a par­tic­u­lar con­cen­tra­tion in plasma, such as 100 ng/mL of the par­ent drug Tetrahy­dro­cannabi­nol (THC), you have very lit­tle effect at one point in time, but at the same drug con­cen­tra­tion (100 ng/mL) at a later time one per­ceives very strong effects.

For this rea­son alone, it should be very very dif­fi­cult for the pros­e­cu­tion to con­vict a mar­i­juana user for an impair­ment based DUID. In fact this whole phe­nom­e­non is why per se drug offenses in terms of DUID are truly unscientific.

But there is more.

The state leg­is­la­tures around the United States have autho­rized the full pros­e­cu­tion and dra­con­ian pun­ish­ment of non-impaired dri­vers as if they were dan­ger­ous drugged dri­vers. The pros­e­cu­tion of mar­i­juana users at per se lev­els for mar­i­juana at or around the time of dri­ving can and is based upon pres­ence (some­times in trace amounts even) of phar­ma­co­dy­nam­i­cally inac­tive metabo­lite 11-nor-9-Carboxy-THC, also known as 11-nor-9-carboxy-delta-9-tetrahydrocannabinol, 11-COOH-THC, THC-COOH, and THC-11-oic acid. Pres­ence of only the phar­ma­co­log­i­cally inac­tive metabo­lite is evi­dence of NON-IMPAIRMENT at the time of the col­lec­tion of the spec­i­men. If any­one only has this inac­tive metabo­lite alone in their spec­i­men no mat­ter what the level, they are not impaired. It is just that sim­ple. This is even more pro­nounced if the spec­i­men is urine which is sim­ply an unpinned his­tory of use at some past time and not ever reflec­tive of impair­ment at the time of collection.

But there is more.

In addi­tion to the unsci­en­tific lia­bil­ity that our leg­is­la­tures have decided to attach to evi­dence of non-impaired dri­ving that we just dis­cussed, the evi­dence of past use of mar­i­juana and the pres­ence of the inac­tive metabo­lite THC-COOH could be far, far removed from last use.

From the abstract of “Uri­nary Elim­i­na­tion of 11-Nor-9-carboxy-9-tetrahydrocannnabinol in Cannabis Users Dur­ing Con­tin­u­ously Mon­i­tored Absti­nence” by Robert S. Good­win, William D. Dar­win, C. Nora Chi­ang, Ming Shih, Shou-Hua Li, and Mar­i­lyn A. Huestis:

The time course of 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol (THCCOOH) elim­i­na­tion in urine was char­ac­ter­ized in 60 cannabis users dur­ing 24 h mon­i­tored absti­nence on a closed research unit for up to 30 days. 6158 indi­vid­ual urine spec­i­mens were screened by immunoas­say with val­ues ≥50 ng/mL clas­si­fied as pos­i­tive. Urine spec­i­mens were con­firmed for THCCOOH by gas chromatography/mass spec­trom­e­try fol­low­ing base hydrol­y­sis and liquid-liquid or solid phase extrac­tion. In 60%, the max­i­mum cre­a­ti­nine nor­mal­ized con­cen­tra­tion occurred in the first urine spec­i­men; in 40%, peaks occurred as long as 2.9 days after admis­sion. Data were divided into three groups, 0 – 50, 51 – 150, and >150 ng/mg, based on the cre­a­ti­nine cor­rected ini­tial THCCOOH con­cen­tra­tion. There were sta­tis­ti­cally sig­nif­i­cant cor­re­la­tions between groups and num­ber of days until first neg­a­tive and last pos­i­tive urine spec­i­mens; mean num­ber of days were 0.6 and 4.3, 3.2 and 9.7, and 4.7 and 15.4 days respec­tively, for the three groups. These data pro­vide guide­lines for inter­pret­ing urine cannabi­noid test results and sug­gest appro­pri­ate detec­tion win­dows for dif­fer­en­ti­at­ing new cannabis use from resid­ual drug excretion.

Mean detection rate each day after first negative <50 ng.mL cannabinoid urine specimen
Mean detec­tion rate each day after the first neg­a­tive (<50 ng/mL) cannabi­noid urine spec­i­men. Cannabis users were sep­a­rated into three groups (0–50, 51–150 and >150 ng/mg) accord­ing to creatinine-normalized THCCOOH con­cen­tra­tions in the first spec­i­men col­lected at admis­sion. Mean detec­tion rate (num­ber of pos­i­tive spec­i­mens in a day/total num­ber of spec­i­mens col­lected that day mul­ti­plied by 100) for the three groups was deter­mined each day after the first neg­a­tive specimen.

The under­ly­ing data that sup­ports the above fig­ure is pre­sented here. The data clearly shows that as long as 28 days days can elapse between the first recorded “neg­a­tive” (really under the limit of detec­tion) test and last pos­i­tive spec­i­men even after total absti­nence. In short due to lipid release a pos­i­tive can occur in chronic users that is arte­fac­tual and not pro­ba­tive (and truly prej­u­di­cial) to the crime sought to be pun­ished which is drug-impaired driving.

And later, the authors of this study conclude:

This study mon­i­tored cannabis users on a closed research unit under con­tin­u­ous med­ical sur­veil­lance dur­ing cannabis absti­nence for up to 30 days. The greater the cre­a­ti­nine cor­rected ini­tial THCCOOH con­cen­tra­tion, the greater the inter­val until the first neg­a­tive and last pos­i­tive spec­i­mens, the greater the win­dow of drug detec­tion and the higher the detec­tion rate of pos­i­tive spec­i­mens. Cannabis users who present with an ini­tial nor­mal­ized THCCOOH con­cen­tra­tion >150 ng/mg can be expected to have detec­tion rates between 60 and 100% for 28 days after the first neg­a­tive urine test. These data increase our under­stand­ing of THCCOOH uri­nary elim­i­na­tion and pro­vide guide­lines for the inter­pre­ta­tion of urine cannabi­noid test results. They also sug­gest appro­pri­ate detec­tion win­dows for dif­fer­en­ti­at­ing new cannabis use from resid­ual drug excre­tion based on cre­a­ti­nine nor­mal­ized THCCOOH urine data.

This phe­nom­e­non proves to be quite prob­lem­atic in pro­ba­tion or parole vio­la­tion hear­ings for alleged mar­i­juana use.  When one is sen­tenced to a term of pro­ba­tion and/or parole typ­i­cally there is a con­di­tion that there is to be no use of illicit drugs (mar­i­juana included). Typ­i­cally the spec­i­men col­lected is urine. Typ­i­cally the pro­ba­tion or parole offi­cer uses the 9 Panel ONESCREEN Multi-Drug Test Cup or some­thing sim­i­lar. Atyp­i­cally the results are sent off for con­fir­ma­tion by GC-MS. The screen­ing tests are pre­sented as truth and not as they should be which is as a screen­ing device with easy, cheap and rapid results with high rates of false pos­i­tive based upon cross-reactivity and lack of true speci­ficity. This same data above is typ­i­cally unknown to the courts or to the probation/parole offi­cers who when con­fronted with a neg­a­tive urine screen then days later are pre­sented with a pos­i­tive urine screen cry foul and accuse the probationer/parolee of use. This may be true in some cases for cer­tain, but the com­bi­na­tion of the lipid release phe­nom­e­non described above, the poor test­ing method, the under­trained and une­d­u­cated pro­ba­tion and parole offi­cer play­ing chemist, and the lack of knowl­edge of all of these lim­i­ta­tions may also result in wrongly accu­sa­tions and false find­ings of vio­la­tions. The issue is that we don’t know.

But there is more.

Plus, we can­not take for granted that the ana­lyt­i­cal chem­istry result is true and cor­rect. The detec­tion of THC and its metabo­lites by screen­ing tests from a bio­log­i­cal sam­ple can pro­vide for false pos­i­tives for any num­ber of rea­sons. Plus, the con­fir­ma­tion (if com­pleted at all) by GC-MS is a very tricky process involv­ing extrac­tion and deriva­ti­za­tion typ­i­cally in terms of the prepar­a­tive chro­matog­ra­phy steps to even make the pos­si­bil­ity of GC-MS detec­tion pos­si­ble. As recently dis­cov­ered and pub­lished in the Jour­nal of Ana­lyt­i­cal Tox­i­col­ogy (January/February 2012, Voume 36, No. 1, pages 61–65) enti­tled “Pro­duc­tion of Iden­ti­cal Reten­tion Times and Mass Spec­tra for Δ9–Tetrahy­dro­cannabi­nol and Cannabid­iol Fol­low­ing Deriva­ti­za­tion with Tri­flu­o­racetic Anhy­dride with 1,1,1,3,3,3-Hexafluoroisopropanol” by Rebecca Andrews and Sue Pater­son informs us of the pos­si­bil­ity of error in exam­in­ing bio­log­i­cal sam­ples (plasma or whole blood) in this cru­cial prepar­a­tive chro­matog­ra­phy step. The THC assays that use the TFAA (tri­flu­o­roacetic anhy­dride) deriva­ti­za­tion meth­ods have been found to result in con­vert­ing cannabid­iol (CBD) to the same deriv­a­tives as THC. The CBD deriv­a­tives have the same GC reten­tion times and mass spec­tra as the THC deriv­a­tives. The authors con­clude that when tar­get­ing and attempt­ing to quan­tify, this deriva­ti­za­tion method must not be used as it can pro­duce a false pos­i­tive in terms of the qual­i­ta­tive mea­sure­ment, and even if objec­tively present, will over­state the true blood concentration.

The inter­pre­ta­tion (elu­ci­da­tion) of the SIM and mass spec­tra often reveals match fac­tor scores and prob­a­bil­ity scores not at 100%. The selec­tion of diag­nos­tic ions and ratios that are thought to reflec­tive of THC is not absolutely set­tled in the ana­lyt­i­cal chemistry/forensic chem­istry world. The quan­ti­ta­tion of THC and its metabo­lites can be per­formed in a metro­log­i­cally unac­cept­able manner.

Yet despite know­ing this, we con­sciously choose to pros­e­cute and con­vict. Sad but true. The emperor has no clothes. False con­vic­tions based not on sci­ence and per­haps even not even ratio­nally related to the harm sought to be avoided abound.

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Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Score one for Science: The DRE program is found to be unreliable and not admissible

On March 8, 2012, in Analysis, Ethics, In The Courtroom, Pharmacology, by Justin J. McShane

As I have blogged before DUID cases should be very dif­fi­cult to pros­e­cute due to the phar­ma­co­log­i­cal dif­fer­ences among us. In this six part post we started to explore all of this:

Part 1. Intro­duc­tion
Part 2. Phar­ma­co­ki­net­ics
Part 3. Phar­ma­co­dy­nam­ics
Part 4. Bioavail­abilty
Part 5. “Free ver­sus Bound Drug“
Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

In a very well-litigated case where the pros­e­cu­tion brought in its very best national experts and the defense had fund­ing and knowl­edge into the DRE pro­gram, the trial court quite clearly found the Drug Recog­ni­tion Expert (DRE) pro­gram to be unsci­en­tific and unre­li­able. As a result the eval­u­a­tion and the con­clu­sion was inadmissible.

The case cita­tion is: State of Mary­land v. Charles David Bright­ful, et al, No. K-10–04-259, Cir­cuit Court for Car­roll County, MD March 5, 2012. The full opin­ion of the court is avail­able here.

What makes this vic­tory even more com­plete for sci­ence is that the court per Mary­land state case law used the much looser Frye stan­dard that gov­erns admis­si­bil­ity of the pros­e­cu­tion evi­dence. So under the Frye stan­dard, the pros­e­cu­tion should have had a much eas­ier time to have the evi­dence gain admissibility.

Here is the hold­ing of the court:

Apply­ing Md. R. 5–702 to the pro­posed DRE tes­ti­mony, the Court finds that a drug recog­ni­tion  expert is not suf­fi­ciently qual­i­fied to ren­der an  opin­ion, that the tes­ti­mony is not rel­e­vant, and the  pro­ba­tive value of the evi­dence is sub­stan­tially  out­weighed by its prej­u­di­cial effect.

Find­ings of Fact:

The DRE Pro­to­col fails to pro­duce an accu­rate and reli­able deter­mi­na­tion of whether a sus­pect is impaired by drugs and. by what spe­cific drug he is  impaired. The DRE train­ing police offi­cers receive does not enable DREs to accu­rately observe the signs and symp­toms of drug impair­ment, there­fore, police offi­cers are not able to reach accu­rate and reli­able  con­clu­sions regard­ing what drug may be caus­ing  impairment.

Six experts tes­ti­fied for the gov­ern­ment. Three tes­ti­fied for the defense: a clin­i­cal phar­ma­col­o­gist, an oph­thal­mol­o­gist, and a psy­chi­a­trist. The defense experts, in sum­mary, were all highly crit­i­cal of dif­fer­ent aspects of “drug recog­ni­tion experts” and the pro­to­col used by DRE’s. All three defense experts tes­ti­fied that the DRE pro­to­col and matrix are not gen­er­ally accepted in the fields of med­i­cine includ­ing specif­i­cally phar­ma­col­ogy, neu­rol­ogy, oph­thal­mol­ogy and psychiatry.

From the opin­ion itself:

Although the DRE pro­gram is uti­lized in 45 states, the pres­ence of the DRE pro­gram does not  equate to wide­spread judi­cial accep­tance by appel­late  courts nor accep­tance in the med­ical community.

Mr. Tower (he is a liai­son from NHTSA and gov­ern­ment expert) fur­ther tes­ti­fied that in addi­tion to  the wide dis­cre­tion in what weight to give the  indi­ca­tors on the matrix, the DRE is not even required  to com­plete the 12-step pro­to­col to reach an opin­ion  as those steps are merely “pre­ferred.” (Tr. 2/14/11  at 95–96). Mr. Tower tes­ti­fied that even if no drugs  at are found in the subject’s blood, the DRE is  “not going to change [their] opin­ion after you get the  blood.” (Id. at 103–04) Mr. Tower stated that the  rea­son there would be no change in the officer’s  opin­ion is that “you are lim­ited on what the lab can  test for.” (Id. at 104) (Empha­sis supplied.)

Part of the defense expert psychiatrist’s testimony:

I have got to tell you, your Honor, DRE is some­thing that’s not fore­most in the mind of those of us who take care of sub­stance  abusers, clin­i­cally or foren­si­cally. Peo­ple  are aware of it. But it’s– no one I  know of, no physi­cian I know of would even con­sider using this matrix or the — even pieces of it in deter­min­ing either whether some­one was impaired on drugs or even more  ridicu­lously to tell which spe­cific drug  cat­e­gory. It’s ridiculous-I can’t empha­size  that enough.

The DRE matrix

The DRE matrix

For both sides it was the most com­pre­hen­sive hear­ing to date look­ing directly at the sci­en­tific reli­a­bil­ity and admis­si­bil­ity of the DRE process.

To validly inter­pret the total­ity of the cir­cum­stances, these cases take experts–real cre­den­tialed phar­ma­col­o­gists with clin­i­cal expe­ri­ence who have dosed folks and real ana­lyt­i­cal chemists. To defend these DUID cases, defense attor­neys need to hire experts. Sadly and incor­rectly most of my col­leagues think they can go with­out. They infre­quently win when they do. If the accused has a knowl­edge­able attor­ney who is schooled and truly under­stands the sci­ence com­bined with real cre­den­tialed experts these cases are quite easy to defend because the sci­ence is wholly on the side of the motorist accused in terms that the gov­ern­ment very rarely has all of the infor­ma­tion nec­es­sary to form a valid conclusion.

The bot­tom line is that claim­ing some­thing is valid and prov­ing it is valid are two sep­a­rate things.

Sci­ence was well-served by this brave and hon­est jurist. Jus­tice was well served by the lit­i­gat­ing attor­neys: Brian DeLeonardo and Alex Cruickshank.

So far, in past hear­ings where it was very lop­sided with the defense not pre­sent­ing experts, the gov­ern­ment could only claim that the DRE process was valid.

Other than per­sonal belief and per­haps anec­do­tal experience/observation, what is there? A bro­ken clock is infi­nitely pre­cise and totally accu­rate twice a day. That coin­ci­dence of obser­va­tion at that exact moment when it is objec­tively cor­rect doesn’t make that clock as a mea­sur­ing device valid, does it?

The source of the empir­i­cal data that was used in the case to inval­i­date the DRE tool came exclu­sively from the stud­ies NHTSA funded or indi­rectly funded. So it is their own research that objec­tively inval­i­dates the tool. It was not defense friendly research that was cited in the hearings.

In short, the cru­cial ques­tion was: “Where is the sci­en­tific val­i­da­tion of this method?” or “Is the DRE pro­to­col proven to be valid for its intended pur­pose which is to opine impair­ment due to source?”

Not only doesn’t the val­i­da­tion stud­ies exist, but the research funded from osten­si­bly pro-prosecution quar­ters fal­si­fies the hypoth­e­sis that it could be a use­ful tool.

I am quite sure that there are a lot of police offi­cers who use the DRE pro­to­col out there who hon­estly believe that it works and is valid. That’s quite fine. It is still the United States of Amer­ica, they are per­son­ally free to believe what­ever they like. I’m all for per­sonal opin­ions. A per­sonal opin­ion doesn’t have to be grounded in sta­tis­tics or val­i­da­tion stud­ies. It is your own.

How­ever, what isn’t just or right is to espouse in court an opin­ion (expert or not) that a tool is valid when it hasn’t been proven as such, and much worse when the evi­dence proves that the method has no valid­ity.  Anyone’s (not the true believ­ers) BELIEF in the use­ful­ness and valid­ity of a tool and/or someone’s anec­do­tal expe­ri­ence is clearly not reli­able sci­en­tific proof of anything.

In essence, the basic ques­tion can be stated thusly: “Is it legit­i­mate to sup­pose that an eval­u­a­tion of a total stranger at one time and one time only with­out know­ing any rel­e­vant phar­ma­co­log­i­cal or phys­i­cal his­tory of the eval­uee by a very min­i­mally trained, non cre­den­tialed per­son, who has never done clin­i­cal rounds, dosed any­one and has no clin­i­cal expe­ri­ence, could be valid?”

A con­vic­tion based upon DRE even if per­fectly exe­cuted is sim­ply a sin against true sci­ence and a sin against justice.

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About the author

Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Pharmacology For Lawyers Part 6: Elucidating Pharmacodynamic Effect from an Analytical Chemistry Result

On May 5, 2011, in Pharmacology, by Justin J. McShane

This is post num­ber six of our six part post on Phar­ma­col­ogy. Our posts will focus on the fol­low­ing top­ics:
Part 1. Intro­duc­tion
Part 2. Phar­ma­co­ki­net­ics
Part 3. Phar­ma­co­dy­nam­ics
Part 4. Bioavail­abilty
Part 5. “Free ver­sus Bound Drug“
Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

Drugged Driving
Drugged Dri­ving

I have posted in essence this part 6 ear­lier here:

False Con­clu­sions and False Con­vic­tions: Attempts of Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result-How Solely an Ana­lyt­i­cal Chem­istry Result in a DUID Pros­e­cu­tion Can­not Sci­en­tif­i­cally Sup­port a Con­clu­sion of Dri­ving Under the Influ­ence of Drugs

With the above prior post, we are now able to take a look at the sta­tis­tics offered by the research, and by the gov­ern­ment with a brand new edu­cated per­specitve. Here is what they say:

  • Com­bined 2006 to 2009 data indi­cate that 13.2 per­cent of per­sons aged 16 or older (an esti­mated 30.6 mil­lion per­sons) drove under the influ­ence of alco­hol in the past year and 4.3 per­cent (an esti­mated 10.1 mil­lion per­sons) drove under the influ­ence of illicit drugs in the same time period
  • The rates of past year drunk dri­ving were among the high­est in Wis­con­sin (23.7 per­cent) and North Dakota (22.4 per­cent); the rates of drugged dri­ving were among the high­est in Rhode Island (7.8 per­cent) and Ver­mont (6.6 percent)
  • When com­bined 2002 to 2005 data are com­pared with com­bined 2006 to 2009 data, the Nation as a whole expe­ri­enced sta­tis­ti­cally sig­nif­i­cant reduc­tions in the rates of drunk dri­ving (from 14.6 to 13.2 per­cent) and drugged dri­ving (from 4.8 to 4.3 per­cent); 12 States saw reduc­tions in drunk dri­ving rates, and 7 saw reduc­tions in drugged dri­ving rates

Accord­ing to SAMSHA:

Percentages of Persons Aged 16 or Older Driving under the Influence of Illicit Drugs in the Past Year, by State: 2006 to 2009
Per­cent­ages of Per­sons Aged 16 or Older Dri­ving under the Influ­ence of Illicit Drugs in the Past Year, by State: 2006 to 2009

Source: http://www.oas.samhsa.gov/2k10/205/DruggedDriving.htm

The ques­tion becomes how does SAMSHA and the fed­eral gov­ern­ment define the term “drugged dri­ving?” Does this mean impair­ment or pres­ence of any mea­sur­able amount of drug (even if it is not phar­ma­col­ogy active)? How do they deter­mine impair­ment? Does it require ana­lyt­i­cal chem­istry con­fir­ma­tion or is it just based upon obser­va­tion or opin­ion of the offi­cer? Is this based upon self-reporting of a sur­vey or num­ber of crim­i­nal charges or num­ber of crim­i­nal convictions?

 
About the author

Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Pharmacology For Lawyers Part 5: Free versus Bound Drug

On May 4, 2011, in Pharmacology, by Justin J. McShane

This is post num­ber five of our six part post on Phar­ma­col­ogy. Our posts will focus on the fol­low­ing top­ics:
Part 1. Intro­duc­tion
Part 2. Phar­ma­co­ki­net­ics
Part 3. Phar­ma­co­dy­nam­ics
Part 4. Bioavail­abilty
Part 5. “Free ver­sus Bound Drug“
Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

When blood sam­ple is ana­lyzed for pur­poses of try­ing to deter­mine pos­si­ble impair­ment in a foren­sic con­text or ther­a­peu­tic ver­sus toxic mon­i­tor­ing in clin­i­cal phar­ma­col­ogy, the total amount of the drug in the blood­stream is that which is recorded (if the analy­sis is cor­rect). How­ever, the large ques­tion becomes,

Is this a truly rel­e­vant measure?

No.

Shock­ing as that may seem at first, the truth is that if you are try­ing to deter­mine pos­si­ble impair­ment or ther­a­peu­tic ver­sus toxic mon­i­tor­ing, then we need to under­stand the con­cept of “free” ver­sus “bound” drug form. Oth­er­wise, if we do not, we may mis­in­ter­pret the phar­ma­co­dy­namic effect based upon an ana­lyt­i­cal mea­sure­ment. We need to exam­ine drug dis­tri­b­u­tion in con­junc­tion with this con­cept of “free” ver­sus “bound” drug form to form a com­plete intel­li­gent pic­ture that involves the con­cepts of Phar­ma­co­ki­net­ics, Phar­ma­co­dy­nam­ics, and Bioavail­abilty.

Drug Disposition
Drug Dis­po­si­tion

For any ingested drug, it ini­tially enters the stom­ach, usu­ally dis­solves, and is then absorbed into the blood­stream. Next, the absorbed drug cir­cu­lates in the vas­cu­lar com­part­ment. An equi­lib­rium mix­ture of free and protein-bound forms is achieved as it courses through the body.

What is of par­tic­u­lar note is that drugs can bind to plasma pro­teins (usu­ally albu­min). While the bind­ing of drugs is reversible, the bind­ing affin­ity of drugs is vari­able. Anionic drugs, which are weak acids, and hydropho­bic drugs, and highly polar drugs have the strongest affin­ity for bind­ing to these pro­teins. If there are two or more drugs in the blood­stream both with a high affin­ity to bind, they will actu­ally com­pete to bind against each other. Only unbound forms of the drug (oth­er­wise known as the “free” form of the drug) can act on tar­get sites in the tis­sues, and may cause pharmacology-relevant effect. On the other hand, bound drugs are always phar­ma­co­log­i­cally inac­tive because they are not free to enter the tis­sue. The brain is the tis­sue of par­tic­u­lar con­cern as that is the epi­cen­ter of impair­ment. The drug pro­duces symp­toms, such as impair­ment, depend­ing strictly on the tis­sue con­tent. In a liv­ing per­son, we can­not sam­ple the brain to get an accu­rate mea­sure of the free form that is in that tis­sue. In other words, we can­not mea­sure blood con­tent of drug in the tis­sue (brain). Instead we must mea­sure what is in the blood­stream which is both the free and the bound form. The blood sam­ple test­ing by way of ana­lyt­i­cal chem­istry can­not dif­fer­en­ti­ate (dis­crim­i­nate) between the free and the bound form. It is just a gross (aggre­gate) mea­sure of both the free and the bound form.

So, as the ana­lyt­i­cal chem­istry analy­sis of the blood mea­sures both the “free” and the “bound” form, and only the free form has the pos­si­bil­ity of being phar­ma­co­log­i­cally active, then we need to be par­tic­u­larly aware of the ratio that a drug has between free and bound to begin to pos­si­bly under­stand the pos­si­bil­ity of impairment.

Of par­tic­u­lar con­cern are chronic users of drugs. For exam­ple, very non­po­lar drugs (termed fat or lipid solu­able) are stored for vary­ing inter­vals in fat tis­sue. [Note, metabo­lites are always more polar than par­ent drugs. As such, there is no such thing as a non­po­lar metabo­lite.] They can then later re-enter the blood from the fat tis­sue. If the con­cen­tra­tion of drug and metabo­lite within the blood is high, as would be the case for a chronic drug user, then the equi­lib­rium favors con­tin­ued adi­pose (fat) tis­sue stor­age. This makes later release into the blood­stream despite actual absti­nence a pos­si­bil­ity. Again, as the ana­lyt­i­cal chem­istry result, as typ­i­cally processed (There are some extra pre-analytical meth­ods avail­able that can be used to sep­a­rate free from bound drug forms. How­ever, these processes  are infre­quently per­formed.), con­tains a mea­sure of both free and bound (and there is no dis­tinc­tion between the two) this release from fat tis­sue could eas­ily be mis­in­ter­preted and pro­vide for a false pos­i­tive despite abstinence.

Protein binding takes place in the bloodstream where there are numerous proteins, such as albumin, to bind the drug as it enters the systemic circulation. These proteins are represented in blue in this diagram; the red and white molecules represent red and white blood cells, respectively. Drug molecules are represented as green circles.

Pro­tein bind­ing takes place in the blood­stream where there are numer­ous pro­teins, such as albu­min, to bind the drug as it enters the sys­temic cir­cu­la­tion. These pro­teins are rep­re­sented in blue in this dia­gram; the red and white mol­e­cules rep­re­sent red and white blood cells, respec­tively. Drug mol­e­cules are rep­re­sented as green circles.

Mar­i­lyn A. Huestis, Ph.D., has writ­ten exten­sively about this type of issue with mar­i­juana. She and her col­leagues have noted that in their research “[e]xceptionally long detec­tion times have been reported for cannabi­noid metabo­lites in the urine of fre­quent drug users dur­ing absti­nence. Dur­ing the ter­mi­nal elim­i­na­tion phase, an indi­vid­ual may pro­duce con­sec­u­tive spec­i­mens that test pos­i­tive, neg­a­tive, and pos­i­tive again over time.” (Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587336/)

Other research that has noted this includes

  • Karschner EL, Schwilke EW, Lowe RH, Dar­win WD, Hern­ing RI, Cadet JL, Huestis MA. Impli­ca­tions of plasma Delta9-tetrahydrocannabinol, 11-hydroxy-THC, and 11-nor-9-carboxy-THC con­cen­tra­tions in chronic cannabis smok­ers. J Anal Tox­i­col. 2009 Oct;33(8):469–77.
  • Dackis CA, Pot­tash AIC, Annitto W, Gold MS. Per­sis­tence of uri­nary mar­i­juana lev­els after super­vised absti­nence. Amer­i­can Jour­nal of Psy­chi­a­try. 1982;139:1196–1198.
  • Kiel­land KB. Uri­nary excre­tion of cannabis metabo­lites. Tidsskr Nor Laege­foren. 1992 May 10;112(12):1585–6.
  • Karschner EL, Schwilke EW, Lowe RH, Dar­win WD, Pope HG, Hern­ing R, Cadet JL, Huestis MA. Do Delta9-tetrahydrocannabinol con­cen­tra­tions indi­cate recent use in chronic cannabis users? Addic­tion. 2009 Dec;104(12):2041–8. Epub 2009 Oct 5.
  • Kelly P, Jones RT. Metab­o­lism of tetrahy­dro­cannabi­nol in fre­quent and infre­quent mar­i­juana users. Jour­nal of Ana­lyt­i­cal Tox­i­col­ogy. 1992;16:228–235.
  • Swa­tek R. Mar­i­juana use:persistence and uri­nary elim­i­na­tion. Jour­nal of Sub­stance Abuse Treat­ment. 1984;1:265–270.
  • Johans­son E, Halldin MM. Uri­nary excre­tion half-life of delta1-tetrahydrocannabinol-7-oic acid in heavy mar­i­juana users after smok­ing. Jour­nal of Ana­lyt­i­cal Tox­i­col­ogy. 1989;13:218–223.
  • Ellis GM, Mann MA, Jud­son BA, Schramm NT, Tashchian A. Excre­tion pat­terns of cannabi­noid metabo­lites after last use in a group of chronic users. Clin­i­cal Phar­ma­col­ogy & Ther­a­peu­tics. 1985;38:572–578.
  • Hawks RL. Devel­op­ments in cannabi­noid analy­ses of body flu­ids: impli­ca­tions for foren­sic appli­ca­tions. In: Agurell S, Dewey W, Wil­lette R, edi­tors. The Cannabi­noids: Chem­i­cal, Phar­ma­co­logic, and Ther­a­peu­tic Aspects. Aca­d­e­mic Press; 1983. pp. 1–12.

Psy­chotropic drugs such as tran­quil­iz­ers, anti­de­pres­sants, antipsy­chotics, mood-altering agents, etc., also cre­ate their own unique prob­lems. These drugs effect users by bind­ing at sites within the cen­tral ner­vous sys­tem (CNS). Because the CNS is quite remote from the blood, such psy­chotropic agents are fre­quently not suit­able sub­jects for drug monitoring.

So, in sum­mary, an accused motorist who insists that he or she had not taken an impair­ing drug yet who has a pos­i­tive blood analy­sis for an impair­ing sub­stance (and in par­tic­u­lar mar­i­juana or other very non­po­lar drugs and non­po­lar drug metabo­lites that may be stored for vary­ing inter­vals in fat tis­sue) may be telling the truth due to the above.

 
About the author

Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Pharmacology For Lawyers Part 4: Bioavailability

On April 28, 2011, in Pharmacology, by Justin J. McShane

This is post num­ber four of our six part post on Phar­ma­col­ogy. Our posts will focus on the fol­low­ing top­ics:
Part 1. Intro­duc­tion
Part 2. Phar­ma­co­ki­net­ics
Part 3. Phar­ma­co­dy­nam­ics
Part 4. Bioavail­abilty
Part 5. “Free ver­sus Bound Drug“
Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

We talked in Part 2 Phar­ma­co­ki­net­ics about the con­cept of absorp­tion. Sim­ply put, absorp­tion is the move­ment of a drug into the blood­stream from the site of admin­is­tra­tion (oral, IV, sub­cu­ta­neous, nasal, etc.). It answers the ques­tion of how it goes from the pre-consumption form of the drug into our blood for later poten­tial affect on the human or pos­si­ble detec­tion in the blood if sam­pled. When deal­ing with DUID cases, it is essen­tial to know a par­tic­u­lar impor­tant part of absorp­tion called bioavailability.

Broadly defined bioavail­abil­ity is used to describe the frac­tion of an admin­is­tered dose of unchanged drug that reaches the sys­temic cir­cu­la­tion. If the drug was admin­is­tered by mouth, the frac­tion that got into the blood could be deter­mined by com­par­ing to the same dose given directly into the blood, i.e., intra­venously (IV).

By def­i­n­i­tion, drugs that are admin­is­tered by way of Intra­venous (IV) deliv­ery have a bioavail­abil­ity of 100%. What becomes trick­ier are those drugs that are not admin­is­tered by IV, but by another route of admin­is­tra­tion. For chem­i­cals taken by routes other than the IV route, the extent of absorp­tion and the bioavail­abil­ity must be under­stood in order to deter­mine whether a cer­tain expo­sure dose will induce impair­ing or even toxic effects or no effect what­so­ever. The con­cept of bioavail­abil­ity may, in part, also explain why the same dose may cause tox­i­c­ity by one route (IV) but not the other (smoking).

Different measured amounts in the blood due to different routes of administration due to the bioavailability of the drug

An exam­ple of dif­fer­ent mea­sured amounts in the blood due to dif­fer­ent routes of admin­is­tra­tion of the same amount of drug, all due to the bioavail­abil­ity of the drug

Exam­ples of drugs and their dif­fer­ent bioavailability:

  • Oxy­codone has a bioavail­abil­ity of about 60–87% when admin­is­tered orally; rec­tal admin­is­tra­tion is reported to be about the same; and when admin­is­tered by intranasal means varies between indi­vid­u­als with a mean of 46%.
  • Pro­pra­nolol has a bioavail­abil­ity of about 26% because 75–85 % is metab­o­lized by the liver before it can reach the cir­cu­la­tion when taken orally.
  • Mor­phine has a bioavail­abil­ity of about 30% because 70% is metab­o­lized via 1st pass effect (metab­o­lism by the liver) if taken orally. Mor­phine is there­fore usu­ally given intra­mus­cu­lar (IM) injec­tion to bypass this mechanism.
  • Codeine–has a bioavail­abil­ity of about 90% when admin­is­tered orally.
  • Cocaine–has a bioavail­abil­ity of about 33% when taken orally; when admin­is­tered by intranasal means is about 60–80%; and when given by nasal spray is about 25–43%.
Bioavailability IV versus oral
Bioavail­abil­ity IV ver­sus oral

There are many fac­tors that affect the bioavail­abil­ity of the orally admin­is­tered drug. This includes, but are not lim­ited to:

  • Rate of dis­so­lu­tion (break­down) of the drug for­mu­la­tion – liquids>solids
  • Sur­face Area of the drug for­mu­la­tion – micro-particle size has great­est sur­face area
  • pH in the gas­troin­testi­nal tract – if a drug is ion­ized it will not be absorbed well from the GI tract
  • Fat (lipid) Sol­u­bil­ity – the more lipid sol­u­ble the greater is absorption
  • Con­cen­tra­tion admin­is­tered – smaller doses tend to be more bioavail­able than large dose
  • Food – drugs com­pete with food in the GI tract for absorp­tion; the more food present the slower the absorption

David M. Ben­jamin, Ph.D. (Clin­i­cal Phar­ma­col­o­gist) writes:

Some Addi­tional Insight into Bioavail­abil­ity and Phar­ma­col­ogy
Bioavail­abil­ity is a mea­sure of both the rate of absorp­tion and the extent of absorp­tion.  The rate of absorp­tion is deter­mined by cal­cu­la­tion of the Tmax, or the time required to reach the peak drug blood con­cen­tra­tion (Cmax), and the extent of absorp­tion is deter­mined by cal­cu­la­tion of the area under the curve (AUC). Regard­less of the shape of the AUC curve, (ie, fast or slow Tmax, low or high Cmax) if the areas inder the curves are the same, the same amount of drug was absorbed. This can be deter­mined eas­ily by cut­ting out the curves and weigh­ing them on a sen­si­tive scale, or by inte­gral cal­cu­lus, for you math nerds.

Many fac­tors impact on bioavail­abil­ity. An oral dose must first dis­in­te­grate and then dis­solve in gas­tric or enteric juices. Most drugs are far bet­ter absorbed from the first 12 inches of the small intestines called the duo­de­num, from the Latin word for 12 (duode­cum). There­fore, fac­tors such as food and low gas­tric pH (indi­cat­ing high acid­ity) slow down gas­tric tran­sit time from the stom­ach into the intestines and the rate of absorp­tion is slowed down. This phe­nom­e­non is well estab­lished with ethanol, which also has the extent of absorp­tion decreased by food in the stom­ach, since the ethanol gets trapped and binds to food and just con­tin­ues past the duo­de­num to lower small intes­tine sites (jejunum and ileum) where absorp­tion is less than in the duodenum.

Oral mor­phine is poorly absorbed by oral admin­is­tra­tion, but it is prob­a­bly due more to its water (aque­ous) sol­u­bil­ity than a first-pass effect. The mor­phine mol­e­cule has both an alco­holic hydroxyl group (-OH) on the 6 posi­tion and a phe­no­lic hydroxyl (-OH) group on the 3 posi­tion of the aro­matic or ben­zenoid ring. The OH groups con­fer water sol­u­bil­ity and the the drug is not able to per­me­ate the pre­dom­i­nantly lipid-soluble (fat-soluble) mem­branes of the GI tract. Addi­tion of a methyl group (-CH3) to the 3 posi­tion changes mor­phine to codeine, masks the OH group and con­fers greater fat-solubility to the mol­e­cule allow­ing it to be more pref­er­en­tially absorbed. How­ever, it does have to be de-methylated back to mor­phine (in the liver) to expert its anal­gesic prop­er­ties. This is done by the CYP 2D6 micro­so­mal enzyme of which there are 5–6 phar­mo­ge­net­i­cally active forms rang­ing from ultra-slow to ultra-fast. Peo­ple who can’t metab­o­lize codeine effi­ciently, also can’t metab­o­lize dexromethor­phan (Robi­tussin cough sup­pres­sant) well, and can become impaired on it on suf­fer dis­so­cia­tive reac­tions. There have been many arrests for DUI-Dextromethorphan.

Once absorp­tion is com­plete, mor­phine has to be dis­trib­uted to the brain (Cen­tral Ner­vous Sys­tem; CNS). Due to its water sol­u­bil­ity, it has been esti­mated that only one mol­e­cule of mor­phine out of 1,000 mol­e­cules cir­cu­lat­ing in the blood actu­ally gets into the brain to relieve pain and exert its array of phar­ma­co­logic activ­i­ties. This is not bioavail­abil­ity, but dis­tri­b­u­tion from blood to the site of the organ where the recep­tors are located.

 
About the author

Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Pharamacology For Lawyers Part 3: Pharmacodynamics

On April 26, 2011, in Pharmacology, by Justin J. McShane

This is post num­ber three of our six part post on Phar­ma­col­ogy. Our posts will focus on the fol­low­ing top­ics:
Part 1. Intro­duc­tion
Part 2. Phar­ma­co­ki­net­ics
Part 3. Phar­ma­co­dy­nam­ics
Part 4. Bioavail­abilty
Part 5. “Free ver­sus Bound Drug“
Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

Phar­ma­co­dy­nam­ics is the study of the time course of drug effects. In other words, what the drug does to the body, good (ther­a­peu­tic) or bad (toxic). Phar­ma­co­dy­namic equa­tions describe the rela­tion­ships between the drug concentration-time pro­file and ther­a­peu­tic, impair­ment and toxic effects.

How do ingested drugs cause reaction? Pharmacodynamics

How do ingested drugs cause reac­tion? Pharmacodynamics

Over­sim­pli­fied, phar­ma­co­dy­nam­ics is the study of how a drug inter­acts with a recep­tors. Sim­ply put, a recep­tor func­tions as a key­hole and the drug is like the key. If the right key finds the right key­hole, then it unlocks what is on the other side. In bio­chem­istry and phar­ma­col­ogy, if the right drug finds the right recep­tor then it opens a neural path towards pos­si­ble affect on the human being. There are dif­fer­ent types of recep­tors, often referred to by the type of inter­ac­tion they have with a drug or drug class, for exam­ple: opi­oid recep­tor, ben­zo­di­azepine recep­tor, nico­tine recep­tor, etc.

In the cen­tral ner­vous sys­tem (CNS) which com­prises the brain and all of the spinal nerves radi­at­ing from the spinal col­umn, prop­a­ga­tion of nerve trans­mis­sion are facil­i­tated at junc­tions called synapse (sim­i­lar to a cir­cuit breaker or fuse in an elec­tri­cal sys­tem). The chem­i­cal that facil­i­tates the nerve trans­mis­sion at the synapse is termed a neu­ro­trans­mit­ter. Some com­mon neu­ro­trans­mit­ters are acetyl­choline (Ach), epi­neph­rine (Adren­a­lin®), nor­ep­i­neph­rine, sero­tonin, and dopamine.

  • A neu­ro­trans­mit­ter released from the pre-synaptic cleft has a spe­cific shape to fit into a recep­tor site sit­u­ated in the post-synaptic cleft and cause a phar­ma­co­log­i­cal response such as a nerve impulse being sent. The neu­ro­trans­mit­ter is sim­i­lar to a sub­strate in an enzyme inter­ac­tion. After attach­ment to a recep­tor site, a drug may either ini­ti­ate a response or pre­vent a response from occur­ring. A drug must be a close “mimic” of the neurotransmitter.
  • An ago­nist is a drug which pro­duces a stim­u­la­tion type response. The ago­nist is a very close mimic and “fits” with the recep­tor site and is thus able to ini­ti­ate a response.
  • An antag­o­nist drug inter­acts with the recep­tor site and blocks or depresses the nor­mal response for that recep­tor because it only par­tially fits the recep­tor site and can not pro­duce an effect. How­ever, it does block the site pre­vent­ing any other ago­nist or the nor­mal neu­ro­trans­mit­ter from inter­act­ing with the recep­tor site.
  • Source: http://www.elmhurst.edu/~chm/vchembook/660drugreceptor.html

How Transmitters and Receptors Work

How Trans­mit­ters and Recep­tors Work

One of the most impor­tant aspects of phar­ma­co­dy­nam­ics is to remem­ber that everyone’s response to a drug is dif­fer­ent. If I take 1 mg of Alpra­zo­lam (Xanax), I will have a dif­fer­ent reac­tion than you will.

The causes of this vari­abil­ity in drug response is really mul­ti­fac­eted and per­haps can be best cat­e­go­rized into two broad, yet inter­con­nected, cat­e­gories: (1) sources of vari­abil­ity that are related to the bio­log­i­cal sys­tem of the par­tic­u­lar human being, and (2) sources of vari­abil­ity due to the admin­is­tra­tion of the drug itself to that par­tic­u­lar human being.

Sources of vari­abil­ity that are related to the bio­log­i­cal sys­tem of the par­tic­u­lar human being:

  1. Body size and body mass (vol­ume of distribution)
  2. Gen­der
  3. Chrono­log­i­cal age
  4. Genetics-pharmacogenetics
  5. Gen­eral health of the person
  6. Psy­cho­log­i­cal aspects (e.g., placebo effect)

Sources of vari­abil­ity due to the admin­is­tra­tion of the drug itself to that par­tic­u­lar human being:

  1. Dosage
  2. Potency of the drug.
  3. How the drug is for­mu­lated (e.g., liq­uid, cap­sule, tablet, sus­tained release)
  4. Route of inges­tion (IV, oral, smoked, etc.)
  5. Sin­gle dose (acute) ver­sus main­te­nance (chronic) ver­sus steady state
  6. Phys­i­o­log­i­cal tol­er­ance of the drug (i.e., drug allergy, drug resistance)
  7. Inter­ac­tion with other drugs and other sub­stances that may be present in the body
 
About the author

Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Pharmacology For Lawyers Part 2: Pharmacokinetics

On April 21, 2011, in Pharmacology, by Justin J. McShane

This is post num­ber two of our six part post on Phar­ma­col­ogy. Our posts will focus on the fol­low­ing top­ics:
Part 1. Intro­duc­tion
Part 2. Phar­ma­co­ki­net­ics
Part 3. Phar­ma­co­dy­nam­ics
Part 4. Bioavail­abilty
Part 5. “Free ver­sus Bound Drug“
Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

Phar­ma­co­ki­net­ics is defined as the study of the rate of drug absorp­tion, dis­tri­b­u­tion, and elim­i­na­tion in the body. In brief, phar­ma­co­ki­net­ics is what hap­pens to the drug while in the body. Phar­ma­co­ki­netic stud­ies inves­ti­gate and char­ac­ter­ize how a drug given by dif­fer­ent routes of admin­is­tra­tion, is absorbed, dis­trib­uted, and elim­i­nated with respect to time.

Phar­ma­co­ki­netic equa­tions describe the rela­tion­ships between dosage reg­i­men and the pro­file of drug con­cen­tra­tion in the blood over time.

Pharmacokinetics
Phar­ma­co­ki­net­ics

Phar­ma­co­ki­net­ics can be divided into dis­tinct, but inter­re­lated con­cepts: Absorp­tion, Distribution, Metabolism, and Excre­tion through use of fun­da­men­tal con­cepts of lin­ear kinet­ics referred to as  Com­part­men­tal Mod­el­ing. In this con­cept, blood would be the cen­tral com­part­ment and other sites of dis­tri­b­u­tion within the body (for exam­ple fat, organs, or cen­tral ner­vous sys­tem) would be other com­part­ments. Most drugs can be described as two– or three-compartment body mod­els, that is, two or three lin­ear lines for the log­a­rithm of blood con­cen­tra­tion ver­sus time plots.

An exten­sion of phar­ma­co­ki­net­ics is tox­i­co­ki­net­ics which describes the rela­tion­ship of drugs to their non-therapeutic effect, namely, toxic effects. Knowl­edge of tox­i­co­ki­net­ics enables one to under­stand indi­vid­ual fac­tors that enhance or reduce tox­i­c­ity. Tox­i­co­ki­net­ics helps to explain why some peo­ple sur­vive large quan­ti­ties of a par­tic­u­lar toxin whereas oth­ers suc­cumb to a much smaller amount.

Methods of ADME
Meth­ods of Absorp­tion, Dis­tri­b­u­tion, Metab­o­lism, and Excretion

Drugs, in gen­eral, fall into two dif­fer­ent types of phar­ma­co­ki­netic char­ac­ter­is­tics: (1) Zero order kinetic drugs, and (2) Non-zero order kinetic drugs.

  • Zero order kinetic drugs are defined as those drugs that have a con­stant rate of elim­i­na­tion irre­spec­tive of plasma con­cen­tra­tion. The most famous exam­ple of a zero order kinetic drug is ethanol.
  • Non-zero order kinetic drugs are defined as those drugs that have a rate of elim­i­na­tion pro­por­tional to plasma con­cen­tra­tion.  The elim­i­na­tion rate con­stant (Kel) rep­re­sents the frac­tion of drug elim­i­nated per unit of time. Rate of elim­i­na­tion = con­stant (CL) x Conc.

The absorp­tion, dis­tri­b­u­tion metab­o­liz­ing and elim­i­na­tion of a chem­i­cal are qual­i­ta­tively sim­i­lar in all indi­vid­u­als but in prac­tice occur at dif­fer­ent rates due to fac­tors such as race, age, and sex. Each per­son must be con­sid­ered indi­vid­u­ally and treated accordingly.

[Update on April 25, 2011]: Alfred Staubus, PharmD, PhD and pro­fes­sor emer­i­tus in phar­ma­col­ogy comments:

Very nice intro­duc­tion to phar­ma­co­ki­net­ics. Prop­erly trained clin­i­cal phar­ma­cists have a full year of courses devoted to just phar­ma­co­ki­net­ics. The sub­se­quent addi­tional clin­i­cal phar­macy courses then use the prin­ci­ples of phar­ma­co­ki­net­ics and phar­ma­col­ogy to prop­erly eval­u­ate and dose patients.

Only one minor comment/clarification: The two basic types of drug elim­i­na­tion are first-order phar­ma­co­ki­net­ics and Michaelis-Menten phar­ma­co­ki­net­ics. For Michaelis-Menten elim­i­nated drugs, at very low con­cen­tra­tions, they behave in a pseudo-first-order fash­ion (rate of elim­i­na­tion is pro­por­tional to con­cen­tra­tion — total body clear­ance is essen­tially con­stant); at high con­cen­tra­tions, they behave in a pseudo-zero-order fash­ion (rate of elim­i­na­tion is essen­tially con­stant, inde­pen­dent of drug con­cen­tra­tion — total body clear­ance decreases as con­cen­tra­tion increases). Ethanol is an exam­ple a Michaelis-Menten drug that at “ther­a­peu­tic con­cen­tra­tions” (greater than 0.02 g/dL) behaves in an appar­ent zero-order fash­ion. Below 0.02 g/dL, ethanol no longer behaves as an appar­ent zero-order drug. At extremely high ethanol con­cen­tra­tions, sec­ondary routes of elim­i­na­tion can some­times be seen.

 
About the author

Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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Pharmacology For Lawyers Part 1: Introduction

On April 19, 2011, in Pharmacology, by Justin J. McShane

Together we are going to embark on a multi-part series on this blog much like our ISO 17025 series.

This series will be sur­round­ing the won­der­ful world of phar­ma­col­ogy. Wikipedia has a good def­i­n­i­tion of phar­ma­col­ogy as follows:

Phar­ma­col­ogy (from Greek φάρμακον, phar­makon, “poi­son in clas­sic Greek; drug in mod­ern Greek”; and -λογία, “Study of” –logia) is the branch of med­i­cine and biol­ogy con­cerned with the study of drug action. More specif­i­cally, it is the study of the inter­ac­tions that occur between a liv­ing organ­ism and chem­i­cals that affect nor­mal or abnor­mal bio­chem­i­cal func­tion. If sub­stances have med­i­c­i­nal prop­er­ties, they are con­sid­ered phar­ma­ceu­ti­cals. The field encom­passes drug com­po­si­tion and prop­er­ties, inter­ac­tions, tox­i­col­ogy, ther­apy, and med­ical appli­ca­tions and antipath­o­genic capa­bil­i­ties. The two main areas of phar­ma­col­ogy are phar­ma­co­dy­nam­ics and phar­ma­co­ki­net­ics. The for­mer stud­ies the effects of the drugs on bio­log­i­cal sys­tems, and the lat­ter the effects of bio­log­i­cal sys­tems on the drugs. In broad terms, phar­ma­co­dy­nam­ics dis­cusses the inter­ac­tions of chem­i­cals with bio­log­i­cal recep­tors, and phar­ma­co­ki­net­ics dis­cusses the absorp­tion, dis­tri­b­u­tion, metab­o­lism, and excre­tion of chem­i­cals from the bio­log­i­cal systems.

Pharmacy is different than Pharmacology

Phar­macy is dif­fer­ent than Pharmacology

Phar­ma­col­ogy is not syn­ony­mous with phar­macy and the two terms are fre­quently con­fused. Phar­ma­col­ogy deals with how drugs affect the body and how the body “deals” with drugs that it is exposed to. On the other hand, phar­macy is a bio­med­ical sci­ence con­cerned with prepa­ra­tion, dis­pens­ing, dosage, and the safe and effec­tive use of medicines.

Pharmacology is the studies of drugs

Phar­ma­col­ogy is the stud­ies of drug affect on a per­son and how a per­son “deals” with drugs

In our series of posts we will be focus­ing on sev­eral dif­fer­ent topics:

Part 1. Introduction

Part 2. Pharmacokinetics

Part 3. Pharmacodynamics

Part 4. Bioavailabilty

Part 5. “Free ver­sus Bound Drug”

Part 6. Elu­ci­dat­ing Phar­ma­co­dy­namic Effect from an Ana­lyt­i­cal Chem­istry Result

 
About the author

Justin J. McShane

Harrisburg DUI attorney Justin J. McShane is the President/CEO of The McShane Firm, LLC - Pennsylvania's top criminal law and DUI law firm. He is the highest rated DUI attorney in PA as rated by Avvo.com. Justin McShane is a double Board certified attorney. He is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc. He is also a Board Certified Criminal Trial Advocate by the National Board of Trial Advocacy, a Pennsylvania Supreme Court Approved Agency. Justin McShane is the first and so far the only Pennsylvania attorney to achieve American Bar Association recognized board certification in DUI defense from the National College for DUI Defense, Inc.

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