TounderstandwhatpKaisandhowitworksthereareafewconceptstogetunderourbeltfirst:pH: MosteveryonehasabasicideaofwhatpHisandhowitworks.However,here’salittleexplanationforthoseofyouwhomayneedalittlerefresher:

Hydrogenionscangainorloseprotonsbasedonwhattypeofsolutiontheyarein.Acidicsolutions,asweknow,arefullofH+ions(protons).Ifanacidisputintoabasicsolution(onewithlessprotons)itwillgiveawayits

protonstothatsolution.Ingivingawayprotonsitwillbecomenegativelycharged.Ifweflippedthisaroundanddroppedsomebasicsolutionintoanacidiconethenthebaseswillgainprotonsandthusbecomingpositivelycharged.Thinkofitlikethis:H+ionsdon’tlikebeinglonely;theywanttohangoutwithmoreH+ionssotheyareniceandsharetheirfriends.Theywilleithergiveawaysomefriendsiftheyhavelotsortakesomeiftheyhavefew.

What does pKa mean and why can it influence drug absorption and excretion?

Weknowthatsomethingsareacidicandsomearebasic(oralkali),butwhatdoesthatreallymean?WhenlookingatthepHofasolutionwearelookingatitshydrogenconcentration:§ Anacidicsolutionisasolutionthathasahighconcentrationof

hydrogenions(H+)§ Abasicsolutionontheotherhandisonewithalowconcentrationof

hydrogenions(seeourlittlefriendsbelow)

pHScale

Ionisation/charge: LetssayIwastodropastrongacidsuchasHydrochloricAcid(HCL)intoaglassofwater(neutralpH).TheHCLmoleculewilldissociate(breakup)intoaH+ionandCl-ion.ThiscanalsobetermedastheHCLmoleculebecomescompletelyionisedinwater.Thisalsomeansthatthemoleculesacquireachargeeithernegativelyorpositivelythroughgainingorlosingelectrons.AweakacidontheotherhandsuchasAspirindoesn’tdissociateverywellinwater,ithaslessH+ionstogiveawaytothewatersoitwilldissociateonlypartiallyorbecomepartiallyionised(RSC2017).

pKa: ThisbringsustotheideaofpKa;AfrequentmisconceptionisthatpHandpKaarethesamething,justopposites.pHandpKaarerelated,however

theyarenotthesamething.ThepKavalueisthepHatwhichadrugisfoundtobe50%ionisedand50%notionised.ItisabletotellushowamoleculewillbehavewhenitisputintosomethingwithacertainpHvalue.TheconceptofpKaisderivedfromsomethingcalledtheaciddissociationconstant(Ka).Thisisanumberthatdescribesthedegreethatanacidwilldissociateinwater(liketheabovereactionwithHCL).TheKaisusuallyaveryhighnumberandcanbeinthe10,000,000,000’s,thismakesitprettyinconvenientforustotryandwrapourheadsaroundsoweusepKainstead.ThepKaisthenegativelogarithm*oftheKavalueandsubsequentlyisamuchsmallernumber(ChemGuide2002).TIP:AgeneralruleofthumbisifthepHofasolutionishigh(acidic)thenthepKawillbeasmallernumber,ifthepHofasolutionislowthenthepKawillbealargernumber.Drugs & pKa: TherelevanceofallthispHandpKatalkessentiallycancomedowntodrugsandhowtheyworkinourbody.

Drugsareweakacidsorbases,sowhereadrugendsupandhowitisabsorbedorexcretedisrelatedto3things:1. ThepHofthesolutionthatthedrugisin2. ThepKaofthedrug3. TheconcentrationofthedrugThecellsofourbodyhavemembranessurroundingthemthataremadeoutoflipids.Ioniseddrugs(drugswithcharge)cannotpassthroughthemembranethereforetheyaresolubleinwaterandwillbeexcretedoutthroughtheurine.Non-ioniseddrugscanpassthroughthelipidmembranethusgettingabsorbedintothebodytocreateanaffect(Peterson,M.2013).OurbodiesaremadeupofmanydifferentareasthatallhaveadifferentpH.WeknowthatthestomachhasaverylowpH(around1-3),ourplasmahasasemi-neutralpH(around7.4)andurineanalkalinepH(around8).WealsoknowthepKavaluesofdifferentdrugsandthereforecangainanideaofwhereinthebodyadrugwouldmostlikelybedistributed.Forexample:Letsthinkintermsofsomeoneoverdosingonamedication,forexampleAspirin.WeknowthatAspirinisaweakacidwithapKaof3.5(Roche2007),thereforewecandeducethattheionizationofthedrugwillbegreatestatanalkalinepH.Soifyouthinkaboutit,weneedtogetasmuchdrugaspossibleintotheionisedformsothatitcanbeexcretedfromthebody.WecanreversetheaffectsofoverdosebyalkalizingbodypHsomoreofthetoxicAspirincanbepartitionedintotheurineandexcreted.

“Alogarithmisthepowertowhichanumbermustberaisedinordertogetsomeothernumber”(UOM2004)

References

Ebid,M.,Abdel-Rahman,H.2001.‘PharmacokineticsofPhenobarbitalDuringCertainEnhancedEliminationModalitiestoEvaluateTheirClinicalEfficacyinManagementofDrugOverdose’.TherapeuticDrugMonitoring,vol.23no.3,pp.209-216.

ChemGuide2002,StrongandWeakAcids,viewed29April,<www.chemguide.co.uk/physical/acidbaseeqia/acids.html>

GerweckLE,KozinSV,StocksSJ1999.‘ThepHpartitiontheorypredictstheaccumulationandtoxicityofdoxorubicininnormalandlow-pH-adaptedcells’.BritishJournalofCancer.Vol79,no.5-6.pp.838-842.

MasterOrganicChemistry2016,WalkthroughofAcid-BaseReactions(4)–pKA,viewed1May2018,https://www.masterorganicchemistry.com/2012/05/09/walkthrough-of-acid-base-reactions-4-pka/>

Peterson,M.2013.‘ToxicologicDecontamination’.SmallAnimalToxicology,vol1.no.3,pp.73-83.

Roche,V.2007.‘ImprovingPharmacyStudents'UnderstandingandLong-termRetentionofAcid-BaseChemistry’.AmericanJournalofPharmaceuticalEducation,vol.71.no.6pp.122.

TheRoyalSocietyofChemistry2017.IonisationofDrugMolecules,viewed30April2018,<www.rsc.org/learn-chemistry/resourcedownload/res00000926/cmp00001239/pdf>

UniversityofMinnesota2004,MathReview:UsefulMathForEveryone,viewed1May2018,<http://www.mclph.umn.edu/mathrefresh/logs.html>