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! 1!
PHARMOCOLOGY+–+week+0:+Introduction+to+Pharmacology+and+Principles+of+Pharmacokinetics+!
What%is%a%drug?%#!it!is!a!chemical!substance!with!a!known!structure!when!used!on!a!living!organism!produces!a!biological!
effect!
#!it!is!NOT!a!nutrient!or!an!essential!dietary!ingredient!
!General%Concepts%of%Pharmacology!#!clinical!pharmacology!is:!
% *!the!study!of!drugs!in!healthy!volunteers!and!patients!
! *evaluation!of:!
#!ability!of!the!drug!to!produce!a!desired!result!
#!safety!of!the!drugs!
#!comparative!trials!between!different!forms!of!treatment!
! *surveillance!of!patterns!of!drug!use!and!any!adverse!effects!that!can!occur%%9%the!‘flow’!of!pharmacology!is!as!follows:!! *Drug%dose%administration!! *disintegration%of%the%drug%(also!known!as!pharmaceutical)!
*adsorption,%distribution,%metabolism%and%excretion%of%the%drug%within!the!body!(pharmacokinetics)!!!VERY!IMPORTANT!
! #!this!is!what!the!BODY!does!to!the!DRUG!
! *drug9receptor%interaction!at!the!cellular!level!(pharmacodynamics)!!!VERY!IMPORTANT!
#!this!is!what!the!DRUG!does!to!the!BODY!
#!it!demonstrates!the!physiological!and!biochemical!effects!of!drugs!and!their!mechanism!
of!action!at!either!the!macromolecular,!subcellular!or!organ!system!levels!
! *drug%effect%or%response%(pharmacotherapeutics)!#!this!is!the!application!of!pharmacological!information!together!with!knowledge!of!the!
disease!!!which!allows!the!prevention!or!cure!of!the!a!disease!
!Drug%Nomenclature%#!a!type!of!drug!can!be!named!differently.!It!can!be!called!by!its:!
! *chemical!name!
! *generic!name!(non#proprietary/not!registered)!
! *brand!name!
!
Example:!
Chemical!name!#!N#acetyl#p#aminophenol!
Generic!name!–!paracetamol!
Brand!name!–!Panadol,!Febridol!etc!
!Routes%of%Drug%Delivery%and%Administration%#!the!different!ways!that!a!drug!can!be!administered!include:!
*Oral!#!can!be!done!sublingually!#!this!is!the!most!COMMON!route!of!delivery!as!it!is!!!convenient,!relatively!safe!and!economical!
#!the!disadvantages!of!administering!orally!are!that!it!cannot!be!used!for:!
! ! *drugs!that!can!be!inactivated!by!gastric!acids!
*drugs!with!large!first3pass4effects!(when!a!large!amount!of!drug!is!metabolised!before!it!reaches!the!systemic!circulation)!
*drugs!that!can!irritate!the!gut!! !
*Inhalation%*Topical%–!this!is!applied!directly!to!the!target!area!(i.e.!can!be!in!the!form!of!a!cream!etc)!
#!this!can!also!be!known!as!transdermal!(which!is!when!the!drug!is!applied!on!the!skin!(such!as!in!the!form!of!a!cream!or!patch)!
*Rectal%%
! 2!
*Injection%–!this!can!include:!subcutaneous,!intramuscular,!intravenous!% Advantages% Disadvantages%Intramuscular%
%#!can!be!given!in!a!slow!and!sustained!
way!
!
#!can!be!painful!
#!can!lead!to!muscular!distrophy!
Subcutaneous% #!can!be!given!in!a!slow!and!sustained!
way!
#!cannot!be!used!for!drugs!that:!
*irritates!cutaneous!tissues!
*have!to!be!given!in!high!
volumes!
Intravenous%%
#!bypasses!absorption!to!give!an!
immediate!effect!
#!can!achieve!100%!bioavailability!
#!higher!risk!of!causing!toxicity!
#!more!expensive!to!administer!
compared!to!the!other!ways!
!Pharmcokinetics%#!pharmacokinetics!is!what!the!BODY!does!to!the!DRUG,!and!it!as!follows:!
!
ABSORPTION!!!DISTRIBUTION!!!METABOLISM!!!ELIMINATION!
!
!
!
!!
#!essentially,!the!main!goal!of!the!drug!(after!administration)!is!to!reach!the!blood!circulation/plasma!! *this!is!done!via!absorption!of!the!drug!from!the!gut,!skin,!muscle!etc!#!after!absorption!it!is!distributed!via!the!blood!and!hepatic!circulation/system!to!target!organs!and!eventually!excreted/eliminated/
! 3!
#!pharmacokinetics!is!the!study!of!the!!!
! *DURATION!(time!course)!of!drug!in!the!BODY!(such!as!in!the!plasma,!in!the!tissues!or!urine)!
! *!as!well!as!the!relationship!between!the!DURATION!and!the!DOSE!of!the!drug!given!%
MEC:%minimum!effective!concentration!MTC:!minimum!toxic!concentration!!
Therapeutic%Window:!the!dose/concentration!!of!the!drug!between!
MEC!and!MTC!
*this!is!the!range!of!drug!dosages!which!can!
treat!disease!effectively!without!causing!
toxicity!
%9%Absorption%of%Drugs%*the!different!mechanisms!of!absorption!of!drugs!from!the!GI!tract!include:!
#!passive!diffusion!!!the!drugs!that!uses!these!mechanism!can!be!categorised!into!those!that!are:!
*water#soluble!(these!drugs!move!through!aqueous!channel!or!pores)!
*lipid#soluble!(these!drugs!dissolve!straight!through!the!membrane)!
#!facilitated!diffusion!!!these!require!protein!transporters!
#!active!transport!!!requires!protein!transporters!and!ATP!
#!endocytosis!or!exocytosis!
!
*the!different!factors!that!affect!absorption!of!drugs!include:!
! #!pH%level%at%the%site%of%absorption!!*a!drug!passes!through!a!membrane!more!
readily!in!it!uncharged/unionised!state!
*whether!a!drug!is!charged!or!uncharged,!
depends!on!the!pH!level!at!the!absorption!site!
and!strength!of!the!weak!acids!and!bases!
*!weak%acids!absorbs!better!when!the!pH!(of!the!environment)!is!LESS%THAN!pKa!!*weak%bases%absorbs!better!when!the!pH%is!MORE%THAN%pKa!
!
! ! ! weak!acids:!!pH!<!pKa!
! ! ! weak!bases:!pH!>!pKa!
!
*note:!pKa!denotes!the!strength!of!the!weak!acid!/base!!the!larger!the!value!of!the!pKa!the!more!basic!the!drug!is!the!smaller%the!value!of!the!pKa!the!more!acidic%the!drug!is!
! ! *note!2:!highly!acidic!or!basic!drugs!do!not!absorb!well!
! !
#!blood%flow!to%the%absorption%site!#!total%surface%area!that!is!available!for!absorption!!!i.e.!microvilli!in!the!intestinal!surface!
greatly!increases!the!ability!for!absorption!in!comparison!to!that!of!the!stomach!
! #!contact%time!at!site!of!the!absorption!!!i.e.!the!greater!the!contact!time!the!more!absorption!
#exposure%of%drug%to%P9glycoprotein!!!P#glycoproteins!are!multidrug!transembrane!
transported!protein.!!
*this!protein!metabolises!drugs,!THEREFORE!the!higher!the!frequency!and!the!longer!the!
drug!is!exposed!to!this!protein!the!more!drug!is!going!to!be!transported!out!of!the!cell!
!
!Bioavailability!#!bioavailability!is!!!the!fraction!(F)!of!the!administered!drug!that!can!reach!the!systemic!circulation!
!
! 4!
#!it!is!always!in!comparison!to!that!of!drugs!that!is!intravenously!administered!!!as!this!method!is!
considered!to!be!100%!of!the!drug!entering!the!systemic!circulation!
!"#$%$"&$'"&"() = !!"#$!!"#$%!!"#$%!!"!!"#$!"#!!"!!" !×!100!!
#!factors!that!affect!bioavailability!include:!
*first%pass%hepatic%metabolism!#!this!is!a!phenomenon!of!drug!absorption!and!metabolism!which!causes!the!
concentration!of!a!drug!to!decrease!before!it!reaches!the!systemic!circulation!
#!this!is!usually!when!the!drug!enters!the!hepatic!portal!circulation!of!the!liver!before!it!enters!the!systemic!circulation!
#!drugs!that!have!HIGH!first!pass!metabolism!are!metabolised!extensively!!and!have!a!
lower!concentration!when!it!reaches!the!systemic!circulation!and!its!target!
#!examples:!aspirin,!morphine,!propranolol,!lidocaine!
! !
*solubility%of%the%drug!! ! #!depending!on!whether!the!drug!is!hydrophilic!of!lipophilic!! ! #!lipophilic!describes!the!ability!of!the!drug!to!readily!cross!cell!membranes!
#!THEREFORE,!the!drug!should!be!LARGELY!lipophilic,!and!yet!be!SLIGHTLY!hydrophilic!is!
ideal!
! *chemical%instability!! ! #!this!refers!to!the!stability!of!drugs!in!certain!environments!(i.e.!acidic)!
! *drug%formulation%9this!refers!to!how!the!drugs!are!made,!which!then!in!turn!affects!the!dissolution!of!the!drug!and!HENCE!alter!the!rate!of!absorption.!Such!as!its:!
! ! ! *particle!size!
! ! ! *crystal!polymorphism!
*enteric!coating:!a!polymer!barrier!which!is!applied!on!oral!medication!which!
protects!the!drug!against!acidic!environments!etc!
!
#[bioequivalence]!!!this!is!a!term!used!in!p’kinetics!when!two!drugs!are!pharmaceutically!equivalent!
such!that!the!drug’s!bioavailability,!effects,!efficacy!and!safety!are!the!same!
! *example:!different!brands!have!the!same!concentration!etc!of!the!same!drug!
#![therapeutic%equivalence]!!!refers!to!a!drug!that!has!the!same!effect/treatment!of!a!
disease/condition!as!one!or!more!different!drugs!
! *example:!when!different!drugs!produces!the!same!effect!
!Half9life!#![half%life]!!!(t1/2)!this!refers!to!the!time4taken!for!the!concentration!of!the!drug!to!fall!to!one!half!of!its!original!blood!levels!
*short!half!life:!when!the!drug!has!a!shorter4duration4of4action,!as!the!drug!is!quickly!removed!from!the!body!
*long!half!life:!when!the!drug!has!longer4duration4of4action,!removed!slower!from!the!body!!
!Drug%Distribution%!
#[drug%distribution]!!this!refers!to!the!process!by!which!a!drug!
reversibly!leaves!the!blood!stream,!to!the!extracellular!fluid!then!into!the!
cells!of!the!tissues!
! *this!occurs!after!drug4absorption!#!In!intravenous!injections,!there!are!NO!absorption!phase!
#!right!after!injection!of!the!drug,!there!is!a!rapid!fall!in!its!concentration!!!
this!is!the!distribution%phase%#!when!the!elimination%phase%is!reached!when!there!is!an!equilibrium!between!the!plasma!and!the!tissues%
! 5!
#factors!that!affects!drug!distribution!include:!
*blood%flow!!!brain!vs!fat.!Adipose!tissues/fat!has!low!blood!flow!and!hence!receives!less!drugs!
in!comparison!with!the!brain!which!has!high!blood!flow!
*capillary%permeability!!!the!differences!in!capillary!structure!(e.g.!continuous!capillaries,!
fenestrated!capillaries)!can!affect!the!ability!of!a!drug!to!cross!from!one!fluid!compartment!to!the!
next!(i.e.!from!the!blood!into!the!extracellular!fluid)!
*molecular%size%! %larger!molecules!have!more!trouble!crossing!barriers!*lipid%solubility%! %especially!through!the!BBB!
*drugs!that!are!lipophilic!can!cross!the!barrier,!polar!and!ionized!molecules!have!trouble!crossing!(they!have!restricted!entry)!
*propofol!and!thiopental!can!both!cross!the!BBB!really!quickly!! *binding%proteins%(plasma%protein%binding)%% % *the!majority!of!drugs!are!reversibility!bound!to!plasma!proteins!called!albumin4! ! *they!can!also!bind!to:!lipoproteins,!glycoproteins!and!beta#globulins!
*these!proteins!acts!as!a!drug4reservoir!such!that!!!‘free!drug’!is!released!from!the!protein!
as!the!concentration!in!the!plasma!drops!to!keep!the!total!drug!concentration!constant!
*depending!on!whether!the!drug!is!acidic!or!basic!they!bind!to!different!proteins:!
! #![acidic!drugs]!!!binds!to!albumin!(examples:!warfarin,!NSAIDs,!sulfonamides)!! #![basic]!!!binds!to!glycoproteins!and!beta9globulin!(example:!quinine)!*the!binding!sites!on!these!proteins!can!be!saturated!
*different!drugs!can!also!COMPETE!for!the!same!binding!site,!SUCH!THAT!drugs!with!a!
higher!affinity!for!the!binding!site!will!displace!those!with!a!lower!affinity!
!
!Volume%of%distribution!*[volume%of%distribution]!!!(Vd)!refers!to!the!fluid!volume!required!to!contain!the!entire!drug!in!the!
body!at!the!same!concentration!measured!in!the!plasma!
! #!it!can!be!represented!by!the!equation:!!!! = !"#!$#%&'%("#!!"!!"#$!!"!!!!!!"#$!!
!
! ! *Co!refers!to!the!concentration!of!drug!in!the!plasma!at!‘time!zero’!(beginning!of!injection)!
#!this!equation!can!be!used!to!determine!the!loading4dose!of!a!drug!!!it!can!be!used!to!determine!
the!dose!of!the!drug!and!toxic!effect!!
!
*most!drugs!can!distribute!into!several!compartments!at!once!
#!these!compartments!include:!plasma,!intracellular!fluid!(cytoplasm),!interstitial!fluid!(a!
component!of!the!ECF)!
*some!drugs!can!distribute!into!one!or!two!compartments:!
! #!example:!heparin!!!very!high!molecular!weight,!can!only!be!found!in!the!plasma!fluid!
! ! *note!–!drugs!that!are!highly!bound!to!protein!only!stays!in!the!plasma!too!!
!Reactions%of%drug%metabolism!9%drug%metabolism!involves!two!kinds!of!biochemical!reaction!!!phase/I%and!phase/II!
%9%phase%I!! *these!involve!reactions!that!are!catabolic!(i.e.!oxidation,!reduction!and/or!hydrolysis)!
! *from!the!different!reactions!the!drugs!can!become!activated,!unchanged!or!inactivated!
*this!phase!often!involves!the!introduction!of!a!hydyoxyl!group!(OH)!into!the!molecule!!!this!
hydroxyl!group!can!then!be!used!as!the!‘point!of!attack’!in!the!conjugating!system!(which!occurs!
in!the!second!phase)!
#!in!other!words,!lipophilic!molecules!are!converted!into!a!more!polar!molecule!by!
introducing!a!functional!group!
! 6!
#!phase%II%% *this!phase!is!the!conjugation4phase!
*the!reactions!that!occur!in!this!phase!are!usually!anabolic/synthetic!!!inactive!products!are!
usually!made!
*!in!this!phase!a!substituent!(such!as!glucoronide)!is!added!to!the!hydroxyl!group!! *the!resulting!products!from!this!phase!are!then!excreted!
! ! #!products!that!are!polar,!water%soluble%or!%inactive%metabolite:!excreted!by!kidney!! ! #!products!that!are!lipophilic:!retained!by!kidney!! *the!products!can!also!be!excreted!via!bile!
!
#!some!drugs!can!bypass!phase!II!altogether,!they!can!directly!enter!phase!II!metabolism.!
! *these!drugs!can!only!be!found!in!faecal!matter!
!
#!the!majority!of!reactions!in!phase!I!and!II!occurs!in!the!liver!
!
#!the!reactions!in!phase!I!involves!cytochrome%P450%(CYP450)!enzymes!! *these!are!hepatic!drug#metabolising!enzymes!(microsomal!mixed#function!oxidases!
*these!enzymes!main!function!is!to!metabolise!drugs!in!the!human!liver!(and!ultimately!facilitate!
elimination)!by!the!means!of!biotransformation!
! *CYP450!has!many!variations,!including:!
9%CYP3A4/5!–!which!is!the!main!enzyme!9%CYP2D6%!#!!when!codeine!binds!to!it,!its!capacity!to!metabolise!substrates!decrease!
% *CYP%inducers4(substances!that!enhances!these!proteins’!functions)!include:!! ! *cigarette!
! ! *alcohol!(chronic!drinking)!
! ! *St!John’s!wort!
! *CYP%inhibitors!include:!! ! *grapefruit!juice!
! ! *cimetidine!
! ! *omeprazole!
!Mode%of%administration!#!intravenous!injection!(not!very!relavent)!
#!oral%dose!! *this!is!when!a!single!dose!will!give!a!single!peak!in!plasma!
! concentration!
*after!the!dose,!the!drug!concentration!will!decline!continuously,!
until!another!dose!is!given!
! *repeated!doses!result!in!oscillations!in!plasma!concentration!
!
!
PHARMACOLOGY+–+week+0:+Pharmacodynamics+!Pharmacodynamics!"!the!philosophy!behind!pharmacodynamics!is:!a!drug!will!not!work!unless!it!is!bound!
*i.e.!the!drug!needs!to!be!able!to!bind!to!its!target!to!be!able!to!produce!an!effect!and!hence!cause!a!physiological3response!!![a!drug!+!drug!target!!!physiological!response]!
!"!most!drug!targets!are!protein!molecules,!these!can!include:!! *receptors,!enzymes,!carrier!molecules!and!ion!channels!
!Binding3site3specificity!"!specificity!between!the!binding!site!and!the!drug!is!reciprocal!!
*such!that!the!drug!can!be!specific!to!the!target,!but!the!target!can!also!be!specific!to!that!particular!drug!!*in!other!words,!individual!classes!of!drugs!bind!only!to!certain!targets,!and!individual!targets!recognise!only!certain!classes!of!drugs!
!"!however!!NO!drugs!are!completely!specific!in!to!their!targets!
*the!majority!of!the!time,!increase!in!doses!of!a!drug!will!affect!targets!other!than!the!principal!one,!which!leads!to!side!effects!
!Receptors!"![receptors]!can!be!defined!as:!
a!target3molecule/protein!which!recognises!endogenous!chemical!signals!(such!as!hormones,!NT,!inflammatory!mediators!etc)!OR!drug!molecules,!in!order!to!produce3physiological3and3biochemical3effects!
!"!in!simpler!terms,!when!a!drug!binds!to!a!receptor!a!pharmacological0effect!is!produced!! *(e.g.!adrenaline!binds!to!β"receptor!!!causing!increase!in!force!and!rate!of!heartbeat)!!
!Affinity3vs3Efficacy3[ligand]!–!a!complex!formed!of!a!molecule!that!has!bound!to!a!receptor!![Affinity]!–!the!ability!of!the!drug!to3bind3to!a!receptor!! *affinity0governs0the0tendency0of00a0drug0to0bind0to0its0receptor0! *HIGH!affinity!=!strong!binding!ability!(has!the!ability!to!produce!effects!at!low!conc.)!! *LOW!affinity!=!weak!binding!ability!(requires!a!higher!conc.!to!produce!an!effect)!! *note:!without!affinity!(when!the!drug!does!not!bind)!there!is!no!efficacy!!! ![Efficacy]!–!the!ability!of!a!drug,!once!bound!to!a!receptor,!to!activate!the!receptor!and!hence!produce3a3pharmacological3response33 *also!known!as!the!intrinsic!activity!
*efficacy!is!pretty!much!the!“product”!that!is!produced!once!the!drug!binds!to!receptor!*efficacy0denotes0the0tendency0of0a0bound0drug0to0activate0its0receptor!(it!is!the!ability!for!the!drug!and!receptor!complex!to!produce!a!response!*different!drugs!can!have!the!SAME!AFFINITY!to!the!receptor!but!DIFFERENT!EFFICACY!
!Agonist3vs3Antagonists3
Agonist3 Partial3Agonist3 Antagonist3
"!a!drug!which!binds!to!the!receptor!and!produces!a!pharmacological!effect!
"!has!affinity!for!receptor!"!but!lower0efficacy!compared!to!another!agonist!acting!at!the!same!receptor!
"!a!drug!which!competes!and!binds!to!the!same!receptor!"!but!does!NOT!activate!the!receptor!
100%!affinity!!100%!efficacy!
100%!affinity!50%!efficacy!
100%!affinity!0%!efficacy!
!"!there!are!different!types!of!agonists,!these!include:!! *agonist!! *partial3agonist:3it!produces!a!submaximum!response!
*inverse3agonist:!molecule!binds!to!a0receptor!in!its!inactive0state!and!produces!a!negative0response/a!response!that!is!opposite!to!that!of!its!corresponding!agonist!
!"!an!antagonist!can!be:!!
competitive!!! "noncompetitive!*competitive3!
"!a!drug!will!selectively!bind!to!a!particular!receptor!WITHOUT!activating!it,!NO!pharmacological!response!will!be!produced!"!it!prevents!the!agonist!from!binding!"!at!a!given!concentration,!the!agonist!occupancy!will!reduce!in!the!presence!of!an!antagonist!!!HOWEVER!by!increasing!the!concentration!of!the!agonist!(in!relation!to!the!antagonist)!the!agonist!occupancy!can!be!restored!!!THEREFORE!making!it!reversible0
! *noncompetitive!!"!this!is!when!the!drug!binds!to!a!receptor!which!is!not!the!receptor!in!which!the!agonist!binds,!NO!pharmacological!effect!will!be!produced!even!if!the!agonist!binds!"!the!effect!is!irreversible,!until!the!antagonist!molecule!is!released!"!increasing!the!conc.!of!the!agonist!still!wont’!be!able!to!produce!a!maximal!effect!when!the!noncompetitive!antagonist!is!present!
*!this!therefore!means!that!in!the!presence!of!a!non"competitive!antagonist!!!the!Emax3of3the3agonists3becomes3‘depressed’3(decreases)!
!!
Dose3response3curve3"![dose3response3curve]!(DRC)!! *also!known!as!a!concentration!response!curve,!concentration!response!relationship!! *the!graph/curve!is!used!to!measure!or!quantify!a!drug"receptor!reaction!
!"!under!normal!circumstances!!!when!a!drug!is!administered,!the3response3will3increase3in3proportion3to3the3dose3until3all3the3receptors3are3occupied3(when!all!binding!sites!are!saturated/when!saturation!is!reached)!*when!this!occurs,!increasing!the!dose!farther!will!NOT!produce!any!further!increases!in!the!response!!!
"!from!a!DRC!different!pieces!of!information!can!be!gathered,!including:!*Emax3–3this!refers!to/denotes!the!maximal&effect!that!can!be!produced!by!a!drug!! *it!is!a!measure!of!the!efficacy3of!a!drug!*EC50!–!refers!to!the!dose!or!concentration3of3a3drug3at350%!of!its!maximal!effect!(Emax)!! *it!is!a!measure!of!the3potency!of!a!drug!!! *note:!potency!refers!to!how!strong!the!effect!of!the!drug!is!*KA3–3refers!to!the!concentration3of3a3drug!that!has!occupied!50%!of!the!total!number!of!receptors!at!equilibrium.!This!is!the!dissocitation0constant.!The3LOWER3the3value,3the3HIGHER3the3affinity3the3drug3has3to3the3receptor3
!!!!
"!Hypobolic3(arithmetic)3vs3Sigmoid3(log3scale)3Hypobolic3 3 LogTscale! 3
3
T3this!type!of!graph!is!difficult!to!analyse!mathematically!
3
T3allows!the!illustration!of!proportionate!doses!at!equal!intervals!"!straighter!lines!"!easier!to!analyse!mathematically!
3T3Drug3efficacy3vs3drug3potency3
"!the!Emax!value!determines!the!drug0effectiveness!! ! *the!Emax!value!refers!to!the!drug’s!maximal0efficacy0
! *the!drug’s!effectiveness!has!nothing!to!do!with!the!drug’s!potency!"!note:!drug!potency!refers!to!the!strength0of!the!effect!(illustrated!by!the!E50)!
!*from!the!graph!it!can!be!seen!that!the:!"Efficacy!for!all!3!drugs!are!the!same!!#!Drug!A!=!Drug!B!=!Drug!C!"!Potency!are!#!Drug!A!>!Drug!B!>!Drug!C!"!this!means!that!the!drugs!are!equip9efficacioius!but!not!equi9potent!!!!!!
"!the!graph!above!also!shows!reversible0competitive0antagonism!! *reversible3competitive3antagonists!causes!the!graph!to!shift3to3the3right!
*it!should!be!noted!that!an!agonist!can!still!produce!a!maximal!effect!in!the!presence!of!a!competitive!antagonist!!#!BUT!a!HIGHER&dose!is!required!!
!"!the!E50!of!all!3!drugs!are!the!same!! *the!potency!of!the!drugs!are!the!same!! *Drug!A!=!Drug!B!=!Drug!C!"!the!Emax!of!the!3!drugs!are!differ!! *Drug!A!>!Drug!B!>!Drug!C!!"!therefore!the!drugs!are!equi"potent!not!equi"efficacious!"!the!graph!on!the!left!also!shows!!!effect!of!noncompetitive3antagonists!on!the!efficacy!(Emax)!of!agonists.!(the!Emax!gets!reduced)!
0"!Occupancy3and3response3curves3! 3Full3vs3partial3agonists3
!"!graph!A:!shows!that!full!agonists!reaches!maximal!effect!at!a!lower!concentration!in!comparison!to!a!
partial!agonist!"!graph!B:!shows!that!full!agonists!produces!a!maximal!effect!at!20%!occupancy,!while!partial!agonist!only!
produces!a!‘submaximal!response’!even!at!100%!occupancy!
Concentration!
%!maximal!response!
"!partial3agonists3and3its3usefulness3! *partial!agonists!acts&as&an&ANTAGONIST&in&the&presence&of&a&full&agonist!!!it!therefore!can!
block!the!full!effect!of!an!agonist!! *by!itself,!the!partial!agonist!produces!a!submaximal!response!Example!1:!Buprenorphine!vs!Morphine!*buprenorphine!(a!opioid!analgesic)!
"!is!a!partial!agonist!"!it!has!a!lower!abuse!potential,!lower!level!of!physical!dependence!and!lower!chance!in!overdosing!!!compared!to!its!full!agonist!counterpart!morphine!
!Example!2:!pindolol!vs!norepinephrine!*pindolol!(partial!agonist)!in!the!presence!of!norepinephrine!(full!agonist)!will!reduce!the!excessive!stimulation!caused!by!the!norepinephrine!
"!in!this!case!the!pindolol!provides!some!agonist!activity!while!blocking!the!activity!of!the!endogenous!full!agonist!at!the!same!time!
!!
DrugTreceptor3interaction!"!drug!to!receptor!binding!is!“transient”!majority!of!the!time!!!such!that!the!drug!molecule!binds!(associates)!and!unbinds!(disassociates)!again!and!again!! *each!time!the!drug!binds!to!the!receptor!a!signal!will!be!triggered!!"!when!there!are!2!different!types!of!drugs!that!acts!on!the!same!receptor!#!they!will!be!able!to!compete0for!the!same!receptor!due!the!transient!binding!that!occurs!! *the!drug!with!a!higher!concentration!will!have!a!greater!chance!of!binding!
!Inverse3Agonists!!
"!normally!when!there!are!no!drugs!present!!!receptors!lies!in!the!resting0state0"however,!there!are!also!‘constitutively0active0receptors’!!!these!are!always!in!an!active0state!regardless!of!the!presence!of!agonists!"!agonists!have!a!higher!affinity!towards!active0receptors,!when!the!agonists!binds!it!shifts!the!equilibrium!to!the!right!"!inverse0agonist!have!a!higher!affinity!towards!inactive0receptors!!
"!an!antagonist!binds!to!both!resting!and!active!receptors!equally!*this!means!that!it!does!not!alter!the!equilibrium!between!the!active!and!resting!states!of!the!receptors!HOWEVER!it!changes!the!efficacy!of!the!agonists!!
!Allosteric3Modulation3"![allosteric3modulation]:!is!the!regulation!of!receptor!by!binding!of!an!effector!molecule!at!an!allosteric!site!(note:!allosteric!site!is!a!binding!site!other!than!the!active!site)!!"![allosteric3modulators]!–!these!molecules!are!neither!agonists!or!antagonists!! *they!essentially!facilitates!the!binding!of!other!molecules!! *there!are!two!types!of!allosteric!modulators:!! ! "!activators!=!effectors/molecules!that!enhance!the!activity!! ! "!inhibitors!=!molecules!that!decreases!activity!
*the!modulators!usually!act!by!causing!a!conformational!change!in!the!receptor!leading!to!a!change!in!the!binding!affinity!of!the!ligand!!!!!
!Other3Antagonisms3"!other!than!competitive!and!noncompetitive!antagonisms,!the!other!types!of!antagonists!include:!
Physiological3(functional)3Antagonism3
"!this!refers!to!when!the!antagonist!as!the!opposite3biological3action!of!the!agonist!"!it!reduces!the!agonists’!effect!by!binding!onto!a!different!receptor,!such!that!!the!antagonist!itself!is!a!type!of!agonist!"!example:!acetylcholine!and!phenylephrine!acting!on!blood!vessels!
Pharmacokinetic3antagonism3
"!this!is!when!the!antagonist!reduces!the!free!concentration!of!drug!that!can!be!found!at!the!target/receptor!"!this!is!done!by!either!reducing!drug!absorption!or!increase!drug!elimination!!"!example:!the!using!of!CYP450!
Chemical3antagonism!
"!chemical!antagonist!combines!with!other!drugs!to!produce!insoluble,!inactive!complexed!"!example:!protamine!sulphate!neutralising!the!action!of!heparin!
Noncompetitive3antagonism!
!"!this!is!when!the!antagonist!doesn’t!block!the!receptor!BUT!the!signal!transduction!process!which!is!suppose!to!initiate!when!agonists!bind!"!example:!calcium!channel!blockers!prevent!the!smooth!muscle!contraction!by!preventing!action!potentials!to!be!generated!
!!
Desensitization/tachyphylaxis!"!desensitization!and!tachyphylaxis!can!be!used!interchangably!"![desensitization]!!!refers!to!when!the!therapeutic!effect!of!a!drug!gradually!diminishes!when!given!continuously!or!repeatedly!! *this!phenomenon!usually!begins!to!occur!after!a!few!minutes!"![tolerance]!!!gradual!decrease!in!the!responsiveness!to!a!drug!"![drug3resistance]!!!loss!of!effectiveness!of!a!drug!(especially!antimicrobial/antibiotic!drugs)!!"!these!3!phenomenon!can!be!caused!by!mechanisms!including:!Change3in3receptors3 Conformational!or!phosphorylatory!changes!in!the!receptor!Loss3of3receptors3 The!internalization!of!receptors!Exhaustion3of3mediators3 When!essential!intermediate!substances!becomes!depleted!Increase3metabolic3degradation3of3drug3 !Physiological3adaptation3 When!homeostatic!response!cancels!out!effects!of!drug!active3extrusion3of3drug3from3cell3 Trasporter!protein!that!is!used!for!the!drug!uptake!changes!!
!Therapeutic3Index3"![therapeutic3index]!(TI)!is!the!concentration!of!a!drug!that!causes!toxicity!in!comparison!to!the!concentration!of!the!drug!that!produces!a!therapeutic!effect!! *essentially,!TI!measures!the!safety!of!a!drug!! *the!larger!the!value!of!the!TI,!the!wider!the!margin!between!!the!effective!dose!and!toxic!doses!! ! "!larger!therapeutic!windows!are!more!desirable!!
!!! !!"!TI!can!be!calculated!by:!!" = ! !"!"!"!"
!!!!!*the!TD50!refers!to!the!dose!required!to!produce!a!toxic!effect!in!half!of!the!population!*ED50!refers!to!the!dose!that!produces!a!therapeutic!effect!in!half!the!population!
PHARMOCOLOGY+–+week+2:+Adrenergic+Drugs+(ANS)+Catecholamines-!"catecholamines"are"all"molecules"derived"from"the"amino"acid"tyrosine"!"catecholamines"found"in"the"body"can"act"as"both"hormones"or"neurotransmitters"!"a"few"different"catecholamines"include:"" *noradrenaline""" *adrenaline"" *dopamine"" *isoproterenol"(a"drug)"
"Noradrenaline-Synthesis-and-Release"!"the"synthesis"of"noradrenaline"is"as"follows:"
TyrosineTyrosine)hydroxylase(rate&limiting&step) !DOPA%→!Dopamine! → Noradrenaline→ Adrenaline!!"
"!"other"enzymes"responsible"for"noradrenaline"synthesis"and"release"include:"
*MAO"(monoamine"oxidase)"enzymes!"can"be"blocked"by"MAO-inhibtors-"*α9adrenoreceptor"!"inhibited"by-α9adrenoreceptor-antagonist--*-α29adrenoreceptor-!""
!"stimulated"by"α29agonists-!"inhibited"by"α29antagonists-
-*β9adrenoreceptors"!"inhibited"by"β9adrenoreceptor--
-Adrenoceptor-Drugs-–-Agonist-and-Antagonist-!"the"main"Adrenoceptor-Agonists"include:"
Direct-Acting- Indirect-Acting-Non9selective-Agonists-(activates-both-α-and-β)-
α9receptor-agonists" β29receptor-agonists-(these"are""β2"inhaled"agonists)"
!"Amphetamine"!"Tyramine"!Ephedrine"!"cocaine"
"
!"noradrenaline"!"adrenaline"!"isoproterenol"!"dobutamine"(β1)"
α19selective-!phenylephrine"
α29selective-!clonidine"
Short-Acting-!salbutamol"!terbutaline"
Long-Acting-(12hours)-!salmeterol"!eformoterol"!"indacaterol"
"!"the"main"Adrenoceptor-Antagonists"include:"Non9selective-Antagonists-(activates-both-α-and-β)- α9receptor-anatgonists" β9receptor-antagonists-
!"labetalol""!"carvediolol"
Non9selective-!phenozybenzamine"!"phentolamine"
α19selective-!"prazosin"!"terazosin"
Non9selective-!"propranolol"!pindolol"
!"oxprenolol"β19selective"
!"atenolol"!"bisoprolol"!metoprolol"!nebivolol"
"Adrenergic-Receptors"!"also"known"as"adrenoceptors"!"there"are"2"main"types"of"adrenergic"receptors:"" *-α-receptors-- *-β-receptors"!"ALL"adrenergic"receptors"are"""g"protein*coupled*receptors""!"the"agonist-potency"when"the"receptors"are"stimulated"by"agonists"are"as"follows:"" *"α"="noradrenaline">"adrenaline">isoprotenernol"" " [note:"this"means"that"noradrenaline"causes"the"strongest"effect]"" *"β="isoprotenernol">"adrenaline">"noradreanline""[α-Receptors]-9"there"are"2"main"α!receptors"subtypes,"which"are:"" *"α1-="Gq-receptor-- *-α2-=-Gi-receptor-" General-Location- Mechanism/Action- Effects/Response-α1" Smooth"muscles"
(including"blood"vessels)"
Gq"!"activation"of"PLC"!"hence"increasing"[Ca2+]"
!"vasoconstriction"(causing"increase"in"BP)"!"GI"tract"smooth"muscle"relaxation"!"salivary"secretion"!"glycogenolysis"
α2" !"Parasympathetic"presynaptic"receptors"!"platelets"
Gi"!"inhibition"of"AC"!"hence"decrease"in"[Ca2+]"
!"inhibition"of"NT"release"(NA,"ACh)"!"responsible"for"feedback"control"of"NA"release"!"inhibition"of"insulin"release"!"platelet"aggregation"
"!"α2-receptors"are"also"responsible"for"the"‘negative-feed-back’"of"NA-release""!"after,"NA"is"released"it:"
1."binds"to"α2-receptors"which"then"inhibits"adenylate-cyclase"and"prevents"it"from"causing"further"release"of"NA"2."binds"to"postsynaptic"receptors""
---"
-[β-Receptors]"!"there"are"3"subtypes"of"β!receptors:"β1,-β2-and-β3"" *they"are"ALL"Gs9receptors"" General-Location- Mechanism/Action- Effects/Response-β1" Heart"
Gs"!"stimulation"of"AC"!"hence"increase"in"[Ca2+]"and"stimulation"PKA"
!"+ve"inotropic"effect"(force"of"contraction)"!"+ve"chronotropic"effect"(HR)"!"+ve"dromotropic"effect"(conduction"speed"of"AV"node)"
β2" !"Lungs"!"Smooth"muscles"
!"bronchodilation"!"vasodilation"!"visceral"smooth"muscle"relaxation"!"glycogenolysis"!"muscle-tremors""!"decrease"in"intraocular"pressure"
β3- !"Adipose"tissue"(metabolism)"
!"lipolysis"
!"note:"stimulation"of"the"β2-receptor"reduces"histamine"release"!"which"is"used"to"treat"anaphylactic"reactions"
Agonist-potency"NA:"α1-=-α2,--β1->-β2"Adren:"α1-=-α2,-β1-=-β2-Isopro:"β1-=-β2->>-α"
"Clinical-Use-and-adverse-effects-of-Adrenoceptor-Agonists"!"the"uses"of"adrenergic"agonists"include:"Adrenaline- !"for"cardiac"arrest"
!"anaphylaxis"!"in"combination"with"local"anaesthetics"to"prolong"their"action*"
Dobutamine- !cardiogenic"shock"β29receptor-agonists-(i.e."salbutamol,"terbutaline,"salmeterol,"eformoterol)"
!asthma"
-*the"COMBINATION"of"adrenaline*and-local*anaesthetics"causes:"" !"reduction"in"blood"loss"" !reduction"in"toxicity"" !"local"tissue"damage""!"the"adverse"effects"caused"by"adrenergic"agonists"include:"" *arrhythmias"" *insomnia"" *headache"" *hyperactivity"" *nausea"" *tremors"!"note:"these"are"all"pretty"much"effects"caused"by"hypersensitivity/activity""
"Clinical-Uses-and-adverse-effects-of-α-Adrenoceptor-Antagonists-9-the"uses"of"the"α-antagonists-include:"Phentolamine- !"decrease"in"total"peripheral"resistance"
!"decrease"in"blood"pressure"!"increase"in"cardiac"output"and"heart"rate"!"can"cause"postural*hypotension*
α19selective-antagonists-(Prazosin,"Terazosin)"
!vasodilation"!"causes"less"severe"tachycardia"and"postural"hypotension"
!"other"clinical"uses"include:"" !"hypertensive"crisis"(can"lead"to"stroke)"" !"chronic"hypertension"" !"peripheral"vascular"disease"" !"erectile"dysfunction""!"the"adverse-effects"caused"by"α-antagonists"include:"" *postural"hypotension"" *vertigo"(dizziness)"" *tachycardia""
"Clinical-Uses-and-adverse-effects-of-β-Adrenoceptor-Antagonists-!"the"clinical"uses"of"β-antagonists-include:"" *angina"pectoris"" *myocardial"infarction"" *heart"failure"" *hypertension"" *glaucoma"(in"the"form"of"timolol-eye-drops)"" *anxiety"control"" *arrhythmias""
"Catecholamine-metabolism-!"catecholamine"metabolism"is"mainly"performed"by"the"following"2"enzymes:"" *Monoamine-oxidase"(MAO)"" *catechol9O9methyl-transferase-(COMT)""[MAO]"!"MAO"is"one"of"the"major"pathways"of"catecholamine"metabolism"!"this"enzyme"is"widely"distributed"in"tissues"
*HOWEVER"a"high"amount"can"be"found"at"NA"nerve"terminals""!the"molecules"that"MAO"metabolises"include:"" *noradrenaline"" *adrenaline"" *dopamine"" *5!HT"(hydroxytyptamine)""
catecholamines, MAO !Aldehydes!Aldehyde'
dehydrogenase !Carboxylic+acids""!there"are"2"subtypes"of"the"MAO"enzyme:"" *MAO9A"="the"MAO!A"reversible"inhibitors"are"used"as"antidepressents"" *MAO9B"="selegeline"(MAO!B"inhibitor)"is"used"in"treatment"of"Parkinsonism"(manifestations"of"
parkinson"disease"symptoms)""[COMT]"9-this"is"the"second"major"pathway"used"for"catecholamine"metabolism"!"they"are"widely"distributed"!"it"metabolises"methoxy"derivatives"of"catecholamines"or"of"deaminated"aldehydes"(formed"by"MAOs)""
"Indirectly-Acting-Adrenoceptor-Agonists-
"!"the"indirect"drugs:"[amphetamine,-tyramine-and-ephedrine]"are"all"structurally"related"to"noradrenaline""!"because"of"their"structural"similarity,"the"indirectly"acting"drugs"!"can"be"taken"up"into"the"pre!synaptic"neuron"vis"the"noradrenaline*transporter"(also"known"as"the"NET)"!"they"then"replace"the"noradrenaline"in"the"synaptic*vesicles.-The"vesicular*monoamine*transporter*(VMAT)-exchanges"NA"for"the"indirect"drugs"!"the"NA"then"accumulates"in"the"cytosol"of"the"pre!synaptic"neuron"!"some"of"the"NA"then"leaves"the"pre!synaptic"neuron"via"the"NET"and"then"binds"to"post"synaptic*receptors-(the"NA"binds"to"both"the"α"and"β-receptors)""
!"the"other"indirect"drug"cocaine,"blocks"the"reuptake"of"the"NA."leaving"more"NA"in"the"synaptic"cleft"and"allowing"it"to"bind"to"the"receptors"
PHARMOCOLOGY+–+week+2:+ANS+–+Cholinergic+Drugs+Neurotransmitters,in,the,ANS,!"the"two"types"of"NT"that"can"be"found"in"the"ANS"include:"" *Acetylcholine"(ACh)", *Noradrenaline,(NA)"
!"Pre!ganglionic"nerve"fibres:"*releases"ACh"!"binds"to"Nicotinic,Receptors""!"Post!ganglionic"nerve"fibres:"*Parasymp"="ALL"releases"ACh"!"Muscarinic"*Symp"="ALL"releases"NA,! ,α,and,β,receptors,
EXCEPT"sweat"glands:,ACh,! ,Musc.,,
Acetylcholine,synthesis,and,release,!"Acetylcholine"is"synthesised"from:"" *"Acetyl!CoA"+"Choline"!"Acetylcholine"(via"the"enzyme"Choline(Acetyl(Transferase("!"Other"enzymes"that"are"related"to"ACh"synthesis"and"release"include:"
"*"Choline,Acetyl,Transferase"(CAT)"""*Presynaptic,nicotinic,ACh,receptor"!"can"be"blocked"by"non2depolarising(blockers("*Acetylcholine,Esterase"!"can"be"blocked"by"substances"such"as"neostigma""*Postsynaptic,nicotinic,ACh,receptor"!""can"be"blocked"by"both"non2depolarising(and"depolarising(blockers("""""""",
"Acetylcholine,Receptors"!"there"are"two"main"types"of"ACh"receptors:"" *Nicotinic,Receptors,, *Muscarinic,Receptors""[Nicotinic]"!"nicotinic"receptors"are"all"ligand'gated'ion'channels"
*when"they"are"stimulated,(depolarisation(occurs"(caused"by"rapid"inflow"of"cations)"!"which"leads"to"action'potential'generation'"
!"there"are"two"main"types"of"nicotinic"receptors:"*Nm,=,Muscle,Type,*Nn,=,Ganglion,Type,
" Location, Mechanism/Action" Response,Nm, Skeletal"muscles"(neuromuscular"junction)" F,excitatory,"
increases"cation"(Na+"and"K+)"
Skeletal"muscle"contraction"Nn, Autonomic"ganglia" !"catecholamine"secretion"
!"post!gang"excitation"
[Muscarinic]"!"muscarinic"receptors"are"all"G1protein'coupled'receptors(!"they"are"all"total"of"5"different"types,"however"only"3"are"used"in"clinics."These"are:"" *M1"="Gq,receptor"" *M2,=,Gi,receptor,, *M3,=,Gq,receptor,, Location, Mechanism/Action, Response,M1, Neuronal" Gq"!"activation"of"PLC"
!"eventually"causing"depolarization"and"excitation"
Neuromodulation"of"NT"
M2, Cardiac" Gi"!"inhibition"of"AC"!"causing"decrease"in"cAMP"and"hence"decrease"in"[Ca2+]"
F,cardiac"inhibition""*decrease"HR"*decrease"in"contractile"forces"
!"neutral"inhibition"M3, Glandular" Gq"(refer"to"above)" Fgastric"and"salivary"secretion"
!"gastro!intestinal"smooth"muscle"contraction"!"ocular"accommodation"!"vasodilation"
,,
Cholinergic,Drugs,!the"main"Cholinergic"Drugs"include:"Muscarinic,Receptor,
Agonists,Muscarinic,Receptor,
(competitive),Antagonists,Acetylcholine,
Esterase,inhibitors*,Neuromuscular,Junction,Blockers,
!"acetylcholine"!"pilocarpine"!"muscarine"!"bethanechol"1carbachol'
1Atropine'!"Scopolamine"!"Ipratropium(1Darifenacin'!Tropicamide"!"Cyclopentolate"
Reversible,FEdrophonium""!"Neostigmine"!Physostigmine"!Pyridostigmine"!,Rivastigmine"!Galantamine"!Donepezil"
Irreversible,F,ecothiophate,
!"organophsophate"
NonFdepolarising,F,mivacuroium"!"vecuroium"!"atracuroium"!"ciscuroium""!pancuroium"!rocuroium'
Depolarising,FSuccinylcholine""(also"known"as"suxamethonium)"
[note:"acetylcholine"cannot"be"used"clinically"as"a"drug"because"of"its"high"susceptibility"to"ACh!esterase]"[note*:"Acetylcholine"esterase"inhibitors"are"also"known"as"Anticholinesterases]""
"Muscarinic,Agonists,and,Antagonists""!"the"main"effects"of"Muscarinic"Agonists"and"Antagonists"can"be"explained"by"!"[DUMBELS]"" Agonists, Antagonists,D, Diarrhoea" Constipation"U, Urination" Urine"retention"M, Miosis"(pupil"constriction)" Mydriasis"(pupil"dilation)"B, Bronchoconstriction" Bronchodilation"E, Emesis"(vomiting)/Excitation" Antimetic"effects"L, Lacrimation"
Dryness"S, Salivation"Sweating"
*note:"the"effects"caused"by"agonists"are"adverse,effects""""
!"other"agonists"effects"include:"Cardiovascular, !decrease"in"CO"
!"decrease"contractility"!"decrease"in"BP"!"general"vasodilation"(caused"by"indirect"releasing"of"nitric"oxide)"
Smooth,Muscle, !"contraction"(i.e."GI"tract"peristalsis)"!"relaxation"of"sphincter"muscles"
Glands, !"secretion"of"ALL"glands"stimulated"by"the"PNS""!"other"antagonist"effects"include:"Cardiovascular, !Tachycardia"
!"no"effect"on"BP"Eyes, !"loss"of"accomodation"(causing"blurred"vision)"
!"increase"in"intraocular"pressure"GI,tract, !decrease"in"motility"CNS, !"mainly"excitatory"effects"
!"low"dose:"mild"restlessness"!"high"dose:"agitation,"disorientation,"hallucination"
"!"the"Major,clinical,use,of"Agonists""" *Acetylcholine,,Pilocarpine,,Carbachol"can"be"used"to:"
!"treat"glaucoma"(an"intraocular"pressure!associated"optic"disorder)"!"reverse"the"effects"of"mydriatics"
" *Pilocarpine"can"be"used"to"treat"!"Xerostomia"" " !"it"increase"parotid,"submandibular"and"sublingual"secretions"" " !"it"has"no"significant"effect"on"BP,"HR"and"cardiac"function"(if"5"to"10mg"are"used)"" " !however"it"can"cause:"sweating,"chills,"nausea"and"dizziness""!"the"Major,clinical/therapeutic,use"of"Antagonists"include:"Atropine, F,to"produce"mydriasis"(pupil"dilation)"
!"to"treat"spastic"disorders"of"GI"tract"!"to"treat"organophosphate(poisoning"!"to"suppress"respiratory"secretions"prior"to"surgery"(a"pre!anaesthetic"drug)"
Scopolamine" !"to"prevent"motion"sickness"Ipratropium" !"used"to"treat"asthma"Darifenacin, !"treat"urinary"incontinence""
"Cholinesterase,(Acetylcholinesterase),!"there"are"two"main"types"of"cholinesterase"drugs:"( *Acetylcholinesterase,=,found"at"acetylcholine"receptors""
it"hydrolyses"ACh"""Choline"and"Acetate"" *Butyrylcholinexterase"="found"in"liver,"skin,"brain"and"GI"tract"smooth"muscles"
it"hydrolyses,"butyrylcholine,"procaine"and"succinylcholine""!"the"action"of"reversible,AChE,inhibitors"Edophonium, Neostigmine,
Physostigmine,Pyridostigmine,
Rivastigmine,Galatamine,Donepezil,
!"short"acting:"2!"10min"!"used"as"a"diagnostic"drug"!"test"for"Myasthenia"gravis"(an"autoimmune"disorder"where"ACh"receptors"are"destroyed"by"antibodies)"!"causes"muscle"weakness"
!longer"acting:"0.5"to"6"hours"!"used"to"treat"Myasthenia"gravis"
!used"to"delay"progression"of"Alzheimer"disease"and"dementia"
"
!"the"action"of"irreversible,AChE,inhibitor""*there"is"only"ONE"irreversible"AChE"inhibitor"""Echothiophate,,*Echothiophate"binds,to,the,–OH"group"found"on"the"active(site"of"the"AChE,"phosphorylating"the"enzyme""causing"the"enzyme"to"become"inactive'*over"time,"if"the"inhibitor"is"not"recmoved,""AGING"(caused"by"loss(of(alkyl(group)"can"cause"the"enzyme"to"become""""irreversibly(inactive"*HOWEVER,"if"Pralidoxime,(PAM),is"used"to"remove"the"Echothiophate"(before"aging)(the"enzyme"would"become"active"again""!""permanent"inactivation"of"the"enzyme"means"!"the"body"is"requires"to"synthesis"new"enzyme"to"restore"them"
"!"the"pharmacological,effects"of"AChE"inhibitors"is"as"follows:"CNS, !"low"dose:"excitation/convulsions"
!"high"dose:"depression,"unconsciousness,"respiratory"failure"ANS,Cholinergic,,synapses,
!"DUMBELS"!"increase"peristaltic"activity"!"bradycardia"(lower"than"average"resting"HR)"!"hypotension"!"decrease"in"intraocular"pressure"
NMJ, !increase"in"strength"of"contration""
" *note:"essentially"the"inhibition"of"AChE"leads"to"significant"increase"in"ACh"concentrations""!"[organophosphate,poisoning]"( *commonly"caused"by"pesticide(poisoning"" *this"type"of"poisoning"causes"SEVERE"‘DUMBELS’"effect"" *the"treatment"for"this"poisoning"include:"
!"maintaining"vital"signs"!"high"dose"of"atropine"(as"atropine"is"an"muscarinic"receptor"antagonist,"it"can"counter"the"DUMBELS)"!"pralidoxime"dose""!"decontamination"
""
Neuromuscular,Junction,Blockers""!"NMJ"blockers"block"cholinergic"transmissions"between"motor(nerve(endings"and"nicotinic(receptors"of"skeletal(muscles,!"they"are"clinically"used"during"surgery"for"producing"complete"muscle"relaxation"without"the"need"of"using"higher"doses"of"anaesthesia"""essentially"muscle,relaxants",F,there"are"two"types"of"NMJ"blockers:"" *nonFdepolarising"–"which"acts"as"antagonists"" *depolarising"–"agonists""[NonFdepolarising,NMJ,blockers]"!"non!depo"NMJ"are"also"known"as"competitive(antagonists"or"stabilising"agents"!they"compete"with"ACh"at"the"NMJ"!"they"block"the"effects"of"ACh"hence"causing"muscle"weakness"(initially)"and"then"flaccid"paralysis"(loss"of"reduced"muscle"tone)"
!"these"drugs"can"be"countered"acted"by"anticholinesterase"drugs"""which"increases"the"concentration"of"ACh"!"and"hence"counteracts"the"effects"caused"by"competitive"antagonists"(check"week"0:"P’dynamic)""!"the"drugs"DO"NOT"cross"the"BBB"and"hence"cannot"affect"mental"status"or"pain""!"the"non!depo"NMJ"blockers"can"be"categorised"according"to"their"duration(of(action"UltraFshort, Short, Intermediate, Long,Succinylcholine"(rapid"onset"–"1"min)""!!"note:"this"is"a"DEPOLARISING"blocker"
Mivacurium" Vecuronium"Atracurium"Cis!atracurium"
pancuronium"
"[Depolarising,NMJ,blockers]"!"these"drugs"have"a"biphasic(effect"when"they"bind:"
*Phase,1"""*the"blocker"causes"depolarisation"at"the"synaptic"membrane,"which"causes"muscle"fasiculations"(small"local"involuntary"muscle"twitches)"
" " !"the"muscle"fasiculations"is"due"to"maintained"depolarisation""" *it"is"then"followed"by"muscle"weakness"and"flaccid"paralysis""
, *Phase,2,"*causes"continued"paralysis"!"the"paralysis"id"due"to"inactivation"of"voltage!gated"Na+"channes"from"over!
depolarisation"*only"ever"seen"at"high"concentrations"
"!"Succinylcholine"(suxamethonium)"is"the"only"clinically"available"agent"" *it"is"resistant"to"acetylcholinesterase"" *it"binds"to"Nicotinic'receptors"in"skeletal"muscle"" *it"can"only"be"given"intravenously"" *low"doses"do"not"cross"the"BBB"" *used"to"treat"epilepsy"" *adverse"effects"include:"" " !"malignant"hyperthermia"(very"high"body"temperature)"" " !"apnoea"(no"muscle"movement"that"allows"inhalation)"" " !"hyperkalemia"(high"potassium"levels),
!
PHARMOCOLOGY+–+week+3:+Cardiovascular+"!the!two!important!regulatory*systems!that!control!the!cardiovascular!system!are:!! 1.!sympathetic*nervous*sytem*! 2.!renin3angiotensin3aldosterone*system*(RAAS)!!
[Sympathetic*nervous*system]!"!the!SNS!is!regulated!by:!
! *!β13adrenoceptors*!!!regulates!the!heart!(especially!the!contractility!of!the!heart)!! **α13*adrenoceptors*!!regulates!the!blood*vessels*(especially!the!vasoconstriction!of!vessels)!!
[Renin3angiotensin3aldosterone*system]!
!
!Antihypertensive*Drugs!"!the!different!antihypertensive!drugs!that!are!available!include:!
! *!β"adrenoceptor!antagonists!
! *!α"adrenoceptor!antagonists!
! *centrally!acting!(α2"agonists) anti"hypertensives!! *drugs!directly!affecting!the!RAAS!
! ! "!ACE!inhibitors!
! ! "!Ang"II!receptor!antagonists!
! *Other!vasodilators!!
"!nitrovasodilators,!calcium!channel!blockers,!potassium!channel!blockers,!diuretics!
!β3adrenoceptor*antagonists*Non3selective*Antagonists*(activates*both*α*and*β)*
Nonselective*β3receptor*anatgonists! Β13receptor*selective*antagonists*
"!labetalol!!
"!carvediolol!
"!propranolol!
"pindolol!
"!oxprenolol!
!
"!atenolol!
"!bisoprolol!
"metoprolol!
"nebivolol!
!
"!their!most!common!effects!on!the!heart!are:!
! *decrease*in*blood*pressure!! **3ve*inotropic*effect** *3ve*chronotropic*effect** *3ve*dromotropic*effect**CLINICAL*USES* ADVERSE*EFFECTS* DENTAL*IMPLICATIONS**angina!pectoris!
*myocardial!infarction!
*heart!failure!
*hypertension!
*glaucoma!(timolol*eyedrops)!*anxiety!control!
*arrhythmias!
*bradycardia!
*hypoglycaemia!
*fatigue!
*reduced!libido!
*drug!withdrawal!(when!drug!is!
stopped!suddenly,!it!can!cause!angina)!
*DON’T!USE!in!asthmatic!patients!
*
*patients!on!nonselective*BBs!should!NOT*receive*LA*that!contain!vasopressors!(i.e.!
epinephrine)!!!it!can!cause!
acute!hypertensive!attacks!
*NSAIDs*used!for!more!than!5!days!reduces!the!effects!of!BBs!!!(+!any!other!hypertensive!drugs)!
Note:!
"!!the!first!choice!drug!for!
hypertension!is!usually!B3blockers!"!for!milder!hypertension!cases!
diuretics!are!usually!used!
!
!α 3Adrenoceptor*Antagonists*Non3selective*Antagonists*(activates*both*α*and*β)* A13receptor*selective*antagonists*
"!labetalol!!
"!carvediolol!
"!prazosin!
"terazosin!
"doxazosin!
!
CLINICAL*USES* ADVERSE*EFFECTS* DENTAL*IMPLICATIONS*"!these!drugs!blocks!post!synaptic!
alpha1"receptors!!!which!causes!
the!lowering+of+blood+pressure!"!the!decrease!in!BP!is!achieved!by:!
! *dilating!blood!vessels,!
which!reduced!peripheral!resistance!
*postural!hypotension!!*headache,!dizziness!
*nausea!
*incontinence!
"!reverses!the!effect!of!adrenaline!
!
!Centrally*Acting*(α23agonists) Anti3hypertensives!"!the!true!Centrally!Acting!α23agonists!include:!! *Methyldopa** *clonidine!(alpha2!selective)!!
"!the!clinical*use*of!the!drugs!are!as!follows:!Methyldopa* "!is!usually!the!drug!of!choice!for!treatment!of!hypertension!during!pregnancy*
"!has!an!indirect!action!
Clonidine* "!acts!directly!on!the!receptors!
"!reduced!peripheral!blood!vessel!tone!
!
"!the!adverse*effects!include:!*postural!hypotension!*dry!mouth!
*CNS!effects:!drowsiness!and!depression!
*fluid!retention!
"!these!drugs!are!not!usually!the!drugs!of!choice,!as!they!have!unwanted/adverse!effects!
!RAAS!"!the!drugs!that!affect!the!renin3angiotensin3aldosterone3system!include:!Angiotensin3converting*enzyme*(ACE)*inhibitors** Angiotensin*II*receptor*antagonists*
"captopril!
"!lisinopril!
"ramipril!
"enalapril!
"fosinopril!
"candesartan!
"losartan!
"valsartan!
"telmisartan!
"irbesartan!
!
[ACE*inhibitors]!"!ACE!inhibitors!are!competitive!inhibitors!
"!they!block!the!pathway!that!converts![Angiotensin*I*! *into*Angioten*II]!"!the!use!of!ACE!inhibitors!leads!to:!
! *decrease!in!vasoconstriction!
! *decrease!in!aldosterone!release!from!adrenal!cortex!
!
CLINICAL*USES* ADVERSE*EFFECTS*"!treatment!of!hypotension*3*treatment!of!heart*failure*3*prevention!of!secondary*myocardial*infarction!"!treats!insulin3dependent*diabetes*
3!persistent!dry!cough!(caused!by!bradykinin)*3*angioedema!"!disturbances!of!taste,!nausea,!vomiting!
"!hyperkalemia!(increase!in!K+!conc.)!
!
[Angiotensin*II*receptor*Antagonists*(ARBs)]*"these!drugs!are!selective!on!Angiotensin*receptor*subtypes!!!AT1!and!AT2!receptors!
! *the!drugs!have!more!effect!at!AT1!receptor!
!
"!overall,!ACE*inhibitors*=!ARBs!!(they!produce!the!same!clinical!effects)!! *EXCEPT,!ARBs!don’t!produce!the!dry*coughs!that!are!produced!by!the!use!of!ACE!inhibitors!!
"!adverse*effects!caused!by!ARBs!include:!! *headache,!dizziness,!muscle!pain,!fatigue!
!
!Calcium*Channel*Antagonists!!
"!the!calcium*channel*blockers*include:!Dihydropyridines*(DHP)* Non3dihydropyridines*(non3DHP)*
"amlodipine!
"felodipine!
"nifedipine!
"minodipine!
"verapamil!
"!diltiazem!
!
!the!action/mechanims!of!CCBs!are!as!follow:!"!in!the!cardiovascular*system!!!the!CCBs!block!Ligand5gated+calcium+channels**"!they!can!also!block!the!calcium!channels!in!other!tissue!types!
! *HOWEVER,!but!this!leads!to!adverse+effects+++++++
+"!ALL!CCBs*causes!the!following!effects:!! *arteriolar!dilation!
! *coronary!artery!dilation!
"!non3DHP!have!these!extra!effects!not!found!in!DHPs,!these!include:!! *"ve!chronotropic!effect!(heart!rate)!
! *"ve!inotropic!effect!(force!of!contraction)!
! *"ve!dromotropic!effect!
!
CLINICAL*USES* DENTAL*IMPLICATIONS*"!verapamils!=!dysrhymthmias!"!nifedipine!or!amlodipine!=!hypertension!"!diltiazem!or!other*DHP!=!angina!prevention!*
3*non3DHP*=!inhibits!metabolism!"!the!effects!of!CCBs*are!NOT*REDUCED!by!the!use!of!NSAIDs!at!the!same!time!
"!gum!hyperplasia!caused!by!Nifedipine,!can!be!
prevented!by!swapping!to!isradipine!!
"!adverse*effects!caused!by!the!CCBs!include:!CCBs*in*general* "headache!
"!flushing!
DHP! "!tachycardia!
Verapamil* "constipation!
"!cardiac!failure!(verapamil!should!NEVER!be!used!with!other!BBs)!
Nifedipine* "!ankle!swelling!
"!gum!hyperplasia!
!
!Diuretics*!
"!different!types!of!diuretics!target!different!location!of!the!renal!tubules:!
* ! Clinical*Use* Unwanted*Effects*Loop*Diuretics**(blocks!the!reabsorption!
of!sodium)!
"!frusemide!"!bumetanide!
"!ethacrynic!acid!
"!oedema!
"!hypertension!
"!acute!hypercalcaeia!
"!hypovolemia!(excessive!
loss!of!platelets)!
"!hypokalemia!(potassium)!
"!hypomagnesemia!
"!hyperuricemia!
Thiazides!(inhibits!sodium"chloride!
symporter!of!the!distal*tubule)!
"hydrochlorothiazide*"!chlorthalidone!
"!indapamide!
"!hypertension!
"mild!heart!failure!
"!severe!oedema!
"!hypokalemia!
"!hyperuricaemia!
!
Potassium3sparing*diuretics!(inhibits!sodium"
chloride!symporter!of!
the!collecting!tubules,!K+!
channels!not!affected)*
"!spironolactone*"!amiloride!
"!used!together!with!
thiazide!diuretics!
"!prevents!
hypokalemia!
"!heart!failure!
"!hyperkalemia!
"!GI!tract!disturbances!
"!causes!androgen!like!
effects!
Carbonic*Anhydrase!(proximal!tubule)!
"!acetazolamide!"!dorzolamide!
"!brinzolamide!
"!reduces!intra"ocular!
pressure!in!open"
angle!glaucoma!
!
!
"!the!DENTAL*IMPLICATIONS!of!diuretics!include:!! *using!NSAIDs!can!affect!the!diuretics!(which!are!used!to!manage!hypertension)!
*when!long!appointments!that!requires!IV!sedations!!!the!morning!dose!of!diuretic!should!NOT!
be!used!(until!the!appointment!is!complete)!
!Antianginal*Drugs*"!the!3!main!antianginal!drugs!are:!! *calcium!channel!blockers!
! *beta!blockers!
! *nitrates!!Organic*Nitrates*"!the!different!Organic!Nitrate!drugs!include:!
! *Glyceryl!trinitrate!(also!known!as!nitroglycerin)!! *isosorbide!dinitrate!
! *isosorbide!mononitrate!
!
"!the!organic!nitrates!mimics!the!action!of!nitric!oxides!(found!naturally!in!the!body)!!!they!are!
vasodilators!which!relaxes+the+vascular+smooth+muscles*! *[refer!to!handwritten!notes]!
!
"!the!effects/major*actions!of!nitrates!include:!! *dilation!of!all!blood!vessels!
! *redistribution!of!coronary!flow!to!ischaemic!areas!
! *relief!of!coronary!spasm!angina!(hence!they!are!ALWAYS!the!drug!of!choice!to!treat!angina)!
!
"!Nitroglycerin!has!very!poor!oral!bioavailability!!!therefore!the!preferable!way!to!administer!include:!
! *transdermally!via!a!patch!
! *sublingually!–!the!most!common!way!
! *buccal!cavity!
!
!
!
CLINICAL*USES* ADVERSE*EFFECTS* DENTAL*IMPLICATIONS*"!stable!angina!(prevention!
using!sublingual)!
"!unstable!angina!(IV)!
"!acute!heart!failure!(IV)!
"!venodilation!!!causing!postural!
hypotension,!headaches!
"!arterial!dilation!
"!tolerance!
"!drug!interactions!(when!2!types!of!
vasodilatory!drugs!are!combined)!
"!patients!with!history!of!angina!
can!use:!
*anxiety!reduction!protocol!
*medicate!in!sitting/supine!
position!
*use!physician!prescribed!
nitroglycerin!
!
!Positive*Inotropic*Agents*"!a!positive!inotropic!agent!is!!!Digoxin!! *derived!from!the!plant!foxglove!
!
"!the!main*clinical*use*for!digoxin!are:!! *congestive!heart!failure!
! *arrhythmias!
!
"!the!main*effect*caused!by!digoxin!are:! !
• 3ve*inotropic*effect!(contractility)!• no!chronotropic!and!dromotropic!effect!
• increase!in!vagal!tone!
• decrease!in!sympathetic!tone!
*note:!this!is!the!ONLY!drug!that!only!affects!the!contractility!and!has!no!affect!on!HR!and!AV!node!velocity!
(all!the!other!drugs!affects!all!3!at!once)!
!
"!the!mechanism/action*!of!digoxin!is!as!follows:!
!!
ADVERSE*EFFECTS* DENTAL*IMPLICATIONS*"!cardiac!arrhythmias!(caused!by!calcium!
increase)!
"!increase!vagal!tone!!!blocking!AV!node!
"!GI!tract!disturbances!causing!vomiting,!
nausea!etc!
"!neurological!disturbances!(i.e.!fatigue)!
*
3*digoxin!is!prescribed!less!frequently!now!BUT!if!a!patient!uses!the!drug!!!macrolide!and!tetracycline!
antibiotics!SHOULD!BE!AVOIDED!
*the!drugs!causes!increase!in!digoxin!concentration!
in!the!plasma,!which!can!cause!digoxin!toxicity!
!
!
!
!
!
!
!Antiarrhythmic*Drugs!"!the!different!antiarrhythmic*drugs*can!be!categorized!into!4!different!classes:!CLASS* ! Drug*examples!I! Membrane*stability*agents*(Na+!channel!blockers)!
*slow!down!depolarization!
Ia!–!disopyramide!
Ib*–*lignocaine!!Ic!–!flecainide!
II! Beta3blocking*agents**affects!contractility!
Propranolol!
Esmolol!
Sotalol!
Metoprolol!
III! Potassium*Channel*Blockers**widen!the!action!potential!
Amiodarone!
Sotalol!
IV! Calcium*channel*blockers!*slows!down!conduction!
Verapamil!
diltiazem!
!
"!the!main*effects*!of!the!different!classes!are!as!follows:!! *ALL!classes!!!slow!down!conduction!
! *ALL!classes!!!increase!refractory!period!(the!period!in!which!another!AP!cannot!be!generated)!
! *ALL!classes!!!decrease!in!contractility!
!Anticoagulants!"!the!different!drugs!that!are!used!to!treat!thromboembolism!(when!a!blood!clot!dislodges!and!gets!lodged!in!another!part!of!the!body)!include:!
Category* Action* Effect!Heparin!"!anticoagulant!
"!inactivates!clotting!factors! "!prevents!venous!thrombosis!
Warfarin!"!anticoagulant,!oral!
"!decreases!clotting!factor!synthesis! "!prevents!venous!thrombosis!
Aspirin!"!antiplatelet!drugs!
"!decrease!platelet!aggregation! "!prevent!arterial!thrombosis!
Thrombolytic*drug* "!fibronlysis! "!breaks!down!thrombi!
!
[Heparin]!"other!types!of!heparin*drugs!include:!Low!molecular!weight!heparin!(enoxaparin,!dalteparin)!!
"!the!mechanism/action*of!heparin!is!as!follows:!!
*heparin!allows!the!binding!of!Anti"thrombin!III!(ATIII)!together!with!either:!
! !!Thrombin,!factor!IIa!or!factor!Xa!
*the!binding!effectively!neutralises!the!clotting!factors!and!hence!preventing!
clotting!factors!to!form!
!
*LMW!Heparins!!!binds!primarily!to!factor!Xa!
!
!
!
"!adverse*effects!caused!by!heparin!include:!! *thrombocytopenia!(when!platelet!count!is!reduced)!
! *bleeding!
! *hypokalemia!
"!these!adverse!effects!are!NOT!caused!by!low!molecular!weight!heparins!
!
!
!
!
!
[Warfarin]!"!warfarin!blocks!the!enzyme!Vitamin+K+reductase!"!the!enzyme!is!responsible!for!the!synthesis!of!clotting!factors!(i.e.!VII,!IX!and!X)!
!
"!warafin’s!anticoagulant!effect!is!delayed!when!changes!is!made!to!the!therapy,!it!takes!a!while!for!the!
drug!to!leave!the!system!
"!aspirin!should!NEVER!be!combined!with!warfarin!!
!
"!international*normalized*ratio!(INR)!! *this!ratio!is!used!to!check!on!people!that!are!on!warfarin!
! *an!INR!test!should!be!taken!24!hours!before!a!surgery!for!people!on!warfarin!
! *INR!less!than!2.2!!!no!contraindication,!proceed!with!surgery!
! *INR!2.2"4.0!!!proceed!with!surgery,!use!tranexamic+acid+mouthwash!after!surgery!! *INR!more!than!4.0!!!do!NOT!proceed!with!surgery!
*warfarin!medication!should!NEVER!be!stopped!!!HOWEVER,!those!with!INR!greater!
than!2.2,!a!reduction!in!dose!can!be!requested!
!
[Aspirin]!"!it!is!an!antiplatelet!drug!
"!the!different!antiplatelet!drugs!include:!
! *aspirin!! *clopidogrel!
! *ticlopidine!
"!aspirin,!at:![LOW*doses]!–!antiplatelet!effect![HIGH*doses]!–!affects!prostaglandin!synthesis!
!
[Fibrinolysis]!"!fibrinolysis!refers!to!!!the!degradation!of!blood!clots!
"!refer!to!notes!for!the!mechanism!"!the!different!drugs!that!stimulate!fibrinolysis!are!called!thrombolytic*drugs,!they!include:!! *streptokinase*(has!the!potential!to!cause!hypersensitivity/allergic!reactions)!* *urokinase* ** *alteplase*
!Cholesterol*Synthesis!"!drugs!that!causes!the!decrease!in!blood!cholesterol!are:!competitive*HMG3CoA*reductase*inhibitors.*3*these!drugs!include:!
*Atorvastatin!
! *Fluvastatin!
! *Pravastatin!
*Rosuvastatin!
*Simvastatin!
!
" refer!to!notes!for!mechanism*!
CLINICAL*USES* ADVERSE*EFFECTS*"!hypercholesterolemia*3high!risk!of!coronary!artery!disease!"!mixed!hyperlipidemia!
3*GI!tract!upset!(nausea,!vomiting,!diarrhoea)!"!dizziness,!headache!
"!myositis!(inflammation!of!the!muscle)!
!
"!other!drugs!that!can!prevent!cholesterol!synthesis!include!!
*Cholestyramine,!colestipol*(acts!on!bile!acids)!! ! *clinical*uses*=!hyperlipidemia,!hypercholesterolemia!
! *adverse*effects!=!constipation,!abdominal!pain,!flatulence!!
*Fenofibrate,*gemfibrozil*(acts!on!the!triglycerides)!* *clinical*uses!=!hypertriglyceridemia,!hyperlidemia!! *adverse*effects!=!dry!mouth,!taste!disturbances!(caused!by!the!gemfibrozil)!
PHARMOCOLOGY+–+week+4:+Local+Anaesthetics+Local&anaesthetics!"!the!criteria!for!use!include:!
• Be!nonirritating!to!the!tissues!in!the!area!of!the!injection!!• Produce!minimal!toxicity!(both!local!and!systemic)!• Be!of!rapid!onset!!• Provide!profound!anesthesia!(prevent!pain)!• Be!of!sufficient!duration!!• Be!completely!reversible!!• Be!sterile!!
!"!LAs:!! *interrupts!pain!impulses!to!specific!region!of!the!body!! *completely!reversible"the!agent!does!not!produce!any!residual!effect!!
*block!nerve!conduction!along!the!nerve!axons!and!other!excitable!membranes!that!uses!sodium*channels!as!the!primary!way!of!AP!generation!!
"Lidocaine&is!the!prototypical!LA!agent!(the!basis!of!which!all!LAs!are!formed!from)!!
Amide&and&Ester&LAs!"!LAs!can!be!categorised!into!2!types:!! 1.!amides!! 2.!esters!!"!the!different!amide!and!ester!drugs!are!as!follows:!
Esters& Amides&–Amethocaine&–Cocaine&!
–Lidocaine/Lignocaine!–Bupivacaine!!
–Levobupivacaine!!–Prilocaine!!–Ropivacaine!!–Mepivacaine&&
![Esters]!"!they!are!easily!hydrolysed!by!the!enzyme!pseudo"cholinesterase!"!the!products!that!are!formed!from!the!reaction!is!!!para0aminobenzoic*acid!! *the!para"aminobenzoic!acid!can!cause!allergic!reactions!![Amides]!"!these!are!usually!the!drug!of!choice!"!when!they!are!metabolised,!inactive!by!products!are!formed!and!hence!do!not!cause!allergic!reactions!
!Reaching&the&site&of&action!
" LAs!are!weak!bases!in!the!form!of!salts!with!a!pH&of&4.5<6.0&" !
"!after!injection!!!the!LA!is!quickly!buffered!to!the!pH!of!the!tissue!!"!as!the!LA!target!receptors!are!not!accessible!from!the!outside!of!the!cell!!!the!uncharged!LA!easily!crosses!the!membrane!barrier!into!the!inside!of!the!cell!"!once!inside,!the!LA!becomes!dissociates!into!a!cation!which!can!then!bind!to!the!target!receptors!!"!note:!inflammation!and!infections!DECREASE&the!LA&effect!!
!Mechanism&of&Action!"LAs!bind!directly!to!intracellular!voltage"dependent!sodium*channels!"!this!prevents!the!sodium&ions!from!flowing!into!the!neuron!"!this!in!turn,!prevents!the!potassium&ions!from!flowing!out!"!the!prevention!of!the!sodium/potassium!inflow!and!outflow!prevent!the!depolarization*of*the*nerve!!"!essentially,!the!LA!block!the!nerve!conduction/action!potential!generation!by!reducing!the!influx!of!sodium!ions!into!the!nerve!cytoplasm!"!if!the!sodium/potassium!movement!can!be!inhibited!at!just!a!few!nodes!of!the!neuron!!!then!any!nerve!impulses!generated!cannot!travel!back!to!the!central!nervous!system!!
!"!LAs!block:!! *90%!!!active&sodium!channels!! *10%!!!resting&!"!they!CANNOT!block!resting*sodium!channels!!!!!
!"!the!targets!the!Las!block!first!can!be!categorized!by:!! 1.!use<dependent&blockade&! 2.!size<dependent&blockade!![Use<dependent&blockade]!
" the!nerve!fibers!that!are!firing!are!more!susceptible!" the!LAs!are!more!selective!and!inhibits!the!nerve!fibres!that!are!stimulated!by!the!surgical!
procedure!first!![Size&dependent&blockade]!"!the!order!in!which!the!nerves!are!blocked!are!as!follows:!
Non"myelinated! Small!type!C!fibres! Dull!pain!! Type!Aδ! Sharp!pain!+!Temp!! Type!Aβ! Touch/pressure!Highly!myelinated! Type!Aα! Motor!!
!Order&of&Sensory&function&block&&
"!pain!"!cold!
"!warmth!"!touch!
"!deep!pressure!"!motor!
!!
Toxicities&of&Local&Anaesthetics!" Local!toxicity!can!be!caused!by:!
o Epithelial!tissue!damage!o Nerve!tissue!damage!o Vascular!(systemic)!damage!
!!!
Blocked!first!!!!Blocked!last!!
Sensory!function!loss!Sensory!function!Recovery!
"!the!effects!caused!by!the!different!tissue!damages!include:!Epithelial&Tissue&Damage& Nerve&tissue&damage& Systemic&Damage&<&tissue!edema!(swelling)!"desquamation!"!necrosis!"!decrease!in!wound!healing!
<&anaesthesia!(unconsciousness)!"!paresthesia!(tingly!sensation)!
"!causes!depression!of!the!cardiovascular!system!(when!excessive!amounts!are!absorbed!into!the!cardiovascular!system)!"!it!can!cause:!*decrease!in!contractility!*hypotension!*decrease!in!conduction!rate!*vasodilation!!
&"!central&nervous&system&toxicity!is!can!also!occur!is!the!LA!is!absorbed!systemically!"!depending!on!the!concentration!of!the!LA!absorbed,!different!effects!can!occur:!! *at!LOW!doses!!!CNS!excitement!! ! "leads!to!light!headedness,!nervousness,!dizziness,!drowsiness,!muscle!twitches/tremours!! *at!HIGH&doses!!!CAN!depression!! ! "!leads!to!respiratory!depression!and!respiratory!arrest!(at!extremely!highly!doses)!!"!other!adverse*effects!caused!by!LAs!include:!
*loss!of!visceral!and!skeletal!muscle!tone!!!therefore!LAs!must!be!used!with!caution!when!it!is!known!that!the!patient!as!myasthenia*gravis!(an!autoimmune!disorder!that!leads!to!muscle!weakness!–!caused!by!antibodies!attacking!acetylcholine!receptors)!
!"!signs*from!early&to&late&stages&of!toxicity!is!as!follows:!*!(early)!circum"oral!and!tongue!numbness!
lightheadedness,!tinnitus,!visual!disturbances!muscular!twitching,!convulsions!
*(late)!!!!!unconsciousness,!coma,!respiratory!arrest,!cardiovascular!collapse!!
!Indications&of&Local&Anesthetics!
" the!different!types!of!LAs!include:!o topical&anaesthesia&(surface&anaesthesia)&o infiltration&anaesthesia&o I.V!regional!anaesthesia!o Nerve&block&anaesthesia&o Spinal!anaesthesia!
!"!of!all!the!different!kinds,!only!infiltration!and!nerve!block!anaesthesia!is!used!in!dentistry!! *and!sometimes!Surface!anaesthesia!![Surface&anaesthesia]!"!the!LAs!include:!lidocaine,!Benzocaine,!Tetracaine,!Procaine!!"!A!topical!block!is!accomplished!by!applying!the!anaesthetic!agent!to!skin,!mucous!membrane,!or!cornea!!
*Only!superficial!layer!is!anesthetized!!![Infiltration&anaesthesia]!"Direct!injection!into!subcutaneous!tissues!to!reach!nerve!branches!and!terminals!!
*Used!in!minor!surgery,!e.g.!suturing!of!wound!or!removal!of!foreign!bodies!!*Dental&procedures!!
!"!Most!of!the!LAs!can!be!used!!!!
*Epinephrine!is!usually!added!except!in!fingers!and!toes!!!!!
[Nerve&Block&Anaesthesia]!"!LA!is!injected!close!to!nerve!trunk!to!produce!a!loss!of!sensation!peripherally.!!"!it!can!be!ssed!for!surgery,!dentistry,!analgesia!!"!most!types!of!LAs!can!be!used!(although!the!most!popular!is!still!lidocaine)!!"!this!technique!requires!less!LA!
Vasoconstrictors!!"sometimes!vasoconstrictors!can!be!used!in!conjunction!with!LAs!to&increase&duration!!
*the!duration!of!the!anesthetic!agent!is!prolonged!by!!!decreasing!the!blood!flow!in!the!immediate!area!of!the!injection.!!
!"!the!vasoconstrictors!can!also!decrease*bleeding!in!the!area!where!the!surgical!procedure!is!occurring!!"!the!different!types!of!vasoconstrictors!that!can!be!used!include:!! *adrenaline&& *noradrenaline&& *levonordefrin!!"!the!advantages!and!disadvantages!of!using!vasoconstrictors!include:! ! !Advantages& Disadvantages&<&increase!in!duration!of!action!"!decrease!in!dose!of!LA!needed!"!decrease!risk!of!bleeding!"!increase!intensity!of!nerve!block!
<&increase!risk!of!local!tissue!injury!and!tissue!necrosis!"!delay!in!wound!healing!"!increase!in!cardiovascular!risk!in!susceptible!patients!
!"!contraindications!for!LA!usage!include:!
*Unstable!angina!*Recent!myocardial!infarction!*Recent!coronary!artery!bypass!surgery!*Untreated!or!uncontrolled!severe!hypertension!*Untreated!or!uncontrolled!congestive!heart!failure!
!!!
PHARMOCOLOGY+–+week+5:+Anxiolytic,+Sedative?hypnotic+drugs+Sedative(hypnotics(vs(Anxiolytic!3(Anxiolytics:(are!drugs!that!reduces'excitement!and!calms!the!patient!WITHOUT!inducing!sleep!! *these!are!also!known!as!sedatives!!<!Hypnotics:!drugs!that!induces!and/or!maintains!sleeps!!3(Clinically(recognised(anxiety(disorder!include:!! *acute!anxiety!! *panic!disorders!! *phobic!disorders!! *obsessive!compulsive!disorders!! *generalized!
!!
Week 8 – Antibiotic use in Dentistry
Antibiotic Prophylaxis - refers to the administration of an antibiotic before a dental procedure - it is used to minimize the risk of bacterial infection - it is only given when the risk of infection is high - dental procedures that require prophylaxis:
• Extractions • Periodontal procedures • Implants • Subgingival root scaling • Subgingival root planning • Replanting avulsed teeth
- indication for prophylaxis:
• prosthetic cardiac valve • history of endocarditis • congenital cardiac disease • rheumatic heart disease – indigenous Australians only
- contra-indications:
• antibiotic prophylaxis is not recommended before dental procedures in patients with prosthetic joints o because there is the risk of infection at a prosthetic joint site
Standard Prophylaxis doses for Endocarditis
Pt Group Drug Dose Route Time - No Allergy - Can orally
Amoxycillin OR Ampicillin
2g Oral 1 hr before procedure
- No allergy - Cannot oral
Amoxycillin OR Ampicillin
2g IV/IM IV – 30 mins before
IM – just prior - Allergy to penicillin
- Can oral Clindamycin 600 mg Oral 1 hr before
- Allergy to penicillin - Cannot oral
Clindamycin OR Lincomycin
600 mg IV
Clindamycin – 20 mins infusion prior to
procedure Lincomycin – 1hr infusion prior to
procedure Antibiotic Therapy Amoxycillin x500mg x5hr x5days Phenoxymethylpenicillin x500mg x6hr x5days Clindamycin x300mg x8hr x5days - as sub for patients allergic to penicillin Metronidazole x400mg x12hr x5days For unresponsive/severe infections Metronidazole x400mg x12hr x5days
PLUS EITHER Phenoxymethylpenicillin x500mg x6hr x5days Amoxycillin x500mg x8hr x5days Amoxycillin + Clavulanic Acid x875mg+185mg x12hr x5days
Week 8 – Antibiotics 2
Protein Synthesis Inhibitors - the following are protein synthesis inhibitors:
• Tetracyclines • Aminoglycosides • Macrolides • Chloramphenicol • Lincosamides
Tetracyclines
• Tetracycline • Doxycyclines • Minocyclines • Demeclocyline • Oxyetracycline –
only one not orally active
Chloramphenicol Macrolides • !Erythromycin –
most commonly used
• Clarithryomycin • Azithromycin • Roxithromycin
Lincosamides • Clindamycin • Lincomycin
Aminoglycosides • !Gentamicin • Amikacin • Tobramycin • Streptomycin • Neomycin
Tetracycline !- they are a class of antibiotics with four cyclic rings - they are all bacteriostatic !- they bind to 30S ribosomal subunit to inhibit bacterial protein synthesis - they are a broad spectrum drug !- Tetracycline (specifically doxyclcines) is the drug of choice for:
• Lyme’s disease " caused by tick bites • Chlamydial infection " sexually transmitted disease (azithromycin is alternative) • Mycoplasma pneumonia " pneumonia of people living in close confines (i.e. military camps) • Cholera " caused by ingesting fecally contaminated food/water • Rocky mountain spotted fever " disease, characteristics include: fever, aches in bone&joints
- other Clinical Uses of tetracyclines:
• Doxycycline – given once daily, can be used for patients with renal impairment • Patients with acne
- Adverse effects of tetracyclines:
• !Chelating of Ca2+, which leads to: o Staining of teeth o Dental hypoplasia o Bone deformities
• Nausea, vomiting • !Hepatotoxicity • !Phototoxicity • !Anti-anabolic effect – stunts growth • Vitamin B Deficiency • Superinfections
Chloramphenicol !- binds to 50S ribosomal subunit - broad spectrum - administered orally and IV - Uses: (because it can cause serious haematological toxicity, it should only be used for severe infections)
• !Typhoid (caused by salmonella) – use tetracycline + chloramphemical combo to treat • Meningitis when penicillin cannot be used • !Conjunctivitis – use eyes drops that contain chloramphenicol topically
- Adverse effects of chloramphenicol:
• Bone marrow toxicity • !Gray baby syndrome • Optic neuritis • rashes
Macrolides !- binds to 50S ribosomal subunit – inhibits translocation - at low conc. " bacteriostatic - at high conc. " bactericidal - administered orally - Erythromycin # acid labile (destroyed easily by acid) - Clarithryomycin, azithromycin # acid stable -used in whooping cough - usually given in doses of:
• 500mg tablets x 3 days • 500mg x 1 day + 250 x 4 days
- Adverse effects:
• neausea, vomiting (common with erythromycin) • rashes • jaundice • inhibits cytochrome P450 enzymes " therefore reacts with other drugs and inhibiting their metabolism
Lincosamides - Clindamycin - absorbs well orally - inhibits bacterial protein synthesis - inhibits most gram +ve cocci + anaerobic bacteria - used in
• prophylaxis of endocarditis • staphylococcal bone infections (posteomyelitis)
!- used in combination with macrolides !- used in substitute to penicillin (does not cause hypersensitivity) - adverse effects:
• nausea, vomiting • superinfection • rashes • jaundice • neutropenia • thrombocytopenia – low amount of platelets
Aminoglycosides - they a class of natural or semisynthetic antibiotics !- binds to 30S ribosomal subunit - they are bactericidal - they have a synergism effect when taken together with cell wall inhibitors (penicillin and cephalosporins) - acts on gram –ve bacteria - they are administered parenterally - they do not cross the BBB # but can cross the placenta !- they must be given in a controlled environment !- because of their adverse effects, they are not commonly given !- Adverse effects
• Occurs together o Ototoxicity – irreversible, starts with loss of balance, then loss of hearing (high pitch then low) o Nephrotoxicity
• NMJ blockade
Bacterial DNA affecting drugs Fluoroquinolones
• Nalidixic acid # Urinary Treat Infection • !Ciprofloxacin (short half life) # Uncomplicated UTI • !Norfloxacin (short half life)# complicated UTI, gonorrhea, bacterial prostatitis • Ofloxacin # complicated UTI, gonorrhea, cervicitis • !Moxifloxacin (long half life)# broad spectrum activity (both gram +ve and gram –ve)
- they inhibit replication of bacterial DNA !- they block the activity of bacterial DNA gyrase and DNA topoisomerase - they are bactericidal - administered orally - Adverse effects
• nausea, vomiting • rashes • !Achilles tendinitis (inflammation of tendons) – even more common in elderly and patients who use
corticosteroids • drug interaction
o ciprofloxacin/norfloxacin – interacts with warfarin and cyclosporine
Metronidazole -! mainly used on anaerobes - !administerd orally - adverse effects:
• nausea, vomiting, abdominal cramps • metallic taste
- Tinidazole
• second generation of metronidazole • active against H.pylori
Week 8 – Antifungal Drugs
- the main fungal pathogen involved in oral diseases ! Candida albicans Sites of Action of Antifungal Drugs
Antifungal Drug Classes: Polyenes – binds to ergosterol of the cell membrane Azoles – inhibit enzyme lanosterol demethylase Terbinafine – inhibit squalone epoxidase Caspofungin – inhibits glucal synthase Flucytosine – inhibits DNA synthesis Griseofulvin – impairs polymerization of microtubule protein
Polyene Nystatin Amphotericin
Azole Imidazole - Applied Topically: Miconazole Clotrimazole Triazoles - Applied Topic OR Sym Fluconazole Itraconazole Posaconazole Voriconazole Ketoconazole – not sym/oral
Terbinafine
Caspofungin
Flucytosine
Griseofulvin
Polyenes - " Mechanism of Action: binds to ergosterol in cell wall and forms aqueous pores
• Disrupts active transport mechanisms in the membrane – affects cell membrane permeability • Can be fungistatic or fungicidal
- Nystatin
• Effective against Candidas • Toxic for systemic use • Topically applied on skin • No adverse effects when applied topically
- Amphoterin
• Active against all common fungi that cause systemic infection • Absorbed poorly in gut (not orally administered) • Given as IV – for serious systemic fungal infections • Adverse effects include:
o Host toxicity – can bind to cholesterol of host o Fevers o Nausea, vomiting, diarrhea
- "dosage for oropharyngeal candidiasis (oral thrush):
• Nystatin – 100,000 units x 4time/day x 7-14days • Amphoterin – 10mg tablet under tongue • Miconazole – 2% gel x 4time/day x 7-14 days
o for HIV patients – Miconzaole (using dosage mentioned above) + Fluconazole/Itraconazole
Azoles - Mechanism of Action: blocks synthesis of ergosterol in fungi by inhibiting lanosterol demethylase
• alter cell membrane synthesis - "Clotrimazole and Miconazole
• used: vginal candidias and ringworm - " Miconazole
• oral candidiasis • intestinal fungal infections
- "Ketoconazole
• when taken orally – adverse effects include: o inhibition of CPY450 can occur – which prevents the metabolism of other drugs (drug interference) o nausea, vomiting, abdominal pain o rash o hepatitis o suprrses androgen production in males – cause oligospermia (low sperm count) or gynaecomastia
(breast enlargement) - Fluconazole
• first line therapy for cryptococcal meningitis - Itraconazole
• mucoutaneous candidiasis
Terbinafine - "Mechanism of Action: inhibits squalene epoxidase (enzyme that converts squalene to ergosterol in cell wall)
• hence inhibiting cell wall synthesis - No adverse effects when used topically - Used to treat – onychomycoses (fungal infection of nails), superficial dermatophyte infections
• fungistatic against candida species
Caspofungin - Mechanism of Action: inhibits glucan synthase, which prevents the production of glycan (the main structural polyermre of fungal cell walls) - hence inhibiting cell wall synthesis
Flucytosine - "Mechanism of Action: inhibits DNA synthesis - is only active against yeasts (candida, aspergillus and Cryptococcus species) - "used in systemic infections
• used to treat cryptococco meningitis - only used in combination with amphotericin or fluconazole - "flucytosine + ampicillin – causes synergistic effect when taken together - "not commonly used because of its adverse effects - Adverse effect:
• "bone marrow depression in high doses
Griseofulvin - Mechanism of action: inhibits mictotubule protein - administered orally – has long half-life
• concentrates in skin and nail beds - has been replaced by oral terbinafine (treats nail infections in the past)
Week 9 – Antiviral Drugs
- antiviral drugs are only effective while the virus is replicating HIV reverse transcriptase inhibitors - active against RNA virus Nuceloside Analogue HIV reverse transcriptase inhibitors (NRTIs) Zidovudine Stavudine Lamivudine Abacavir Tenofovir
Non-nuceloside reverse transcriptase inhibitors (NNRTIs) Efavirenz Nevirapine
NRTIs - inhibits HIV reverse transcriptase - !they are analogues of precursors of the natural purine and pyrimidine - adverse effects:
• Nausea, vomiting • Myalgia (muscle pain), myositis (muscle inflammation) • Life threatening heptomegaly • Peripheral neuropathy • Pancreatitis • Lipodystrophy syndrome
NNRTIs - binds to HIV reverse transcriptase at allosteric site – which then prevents other substrate from binding - Adverse effects:
• !Nevirapine – Hepatotoxicity – fulminant hepatitis • drug interactions • nausea, vomiting • headache, drowsiness
HIV Protease Inhibitors - the Drugs include:
• Atazanvir • Indinavir • Darunovir • Rotinavir • Squinavir
- Mechanism of Action: blocks the formation of functionally active proteins - Adverse effects:
• Ritonvair – paraesthesiae (pins-and-needles in the skin) • Metabolic disturbances (hyperlipidemia, insulin resistance, glucose intolerance, lipodystrophy) • Hepatic dysfunction • Drug interactions
!HAART for HIV - HAART = Highly Active Antiretroviral Therapy - it is used to treat HIV/AIDS - uses combinations of = reverse transcriptase inhibitors and protease inhibitors
• The combinations include: o 1PI + 2NRTIs - e.g. atazanavir (PI) + tenofovir (NRTI) + lamivudine (NRTI)
OR o 2NRTIs + 1NNRTI - e.g. Efavirenz (NNRTI) + Tenofovir (NRTI) + lamivudine (NRTI)
Viral DNA polyermase Inhibitors Nucleoside Analogues Aciclovir Ganciclovir Valaciclovir Valganciclovir
Non-nucleoside Analogues Foscarnet Cidofovir
Nucleoside Analogue !- Aciclovir and Valaciclovir treats:
• Low dose = Herpes Simplex virus (cold sores) and Herpes Zoster virus (shingles) • High dose = Cytomegalovirus
!- Ganciclovir treates – Cytomegalovirus - Adverse Effects include:
• Ganciclovir – bone marrow suppression • Sever local phlebitis (inflammation of the veins) • Rashes • Nausea, vomiting • Encephalopathy • !Aciclovir – Nephrotoxicity (when used systemically)
Non-nucleoside Analogues - these are reversible inhibiters of cytomegalovirus and herpes simplex virus - Adverse effects include:
• Naeusea, vomiting • Nephrotoxicity • Headache, tremor, dizziness
Dental Concerns - conditions that are associated with HIV infection that are significant to dentist include:
• Syphilis • Tuberculosis • Persistent generalized lymphadenopathy • Gastro-oesophageal reflux disease • Odynophagia
- treating Herpes Simplex Virus (cold sores) !Severe recurring/systemic Aciclovir 5% cream topically x5 times/day
OR every 4 hours x4 days
Penciclovir 1% cream topically x6 times/day OR every 2 hours
x4 days
Severe primary episodes Aciclovir 400mg orally x5 times/day x7days Valaciclovir 1g z12hr x7days
Week 9 – Anticancer Drugs
- Anticaner drugs are antiproliferative - they affect cell division - they target rapidly divind cells - they are most effective during the S phase of cell cycle - they cause damage to DNA which then initiates apoptosis of the cell !- A therapeutic dose of cytotoxic drug destroy a constant fraction of malignant cells Drugs classes used in Cancer chemotherapy
• !Cytotoxic Agents – Alkylating Agents Antimetabolites Cytotoxic Antibiotics Plant Derivatives
• Hormones • Monoclonal antibodies • Protein kinase inhibitors
Cytotoxic Agents
Alkylating Agents Nitrogen Mustards Cyclophosphamide Ifosfamide Melphalan Chlorambucil Nitrosoueas Carmustine Lomustine Triazines Dacarbazine Buslfan Platinum Compounds Cisplatin Carboplatin
Antimetabolites Folic Acid Anatagonists Methotrexate Pemetrexed Raltitrexed Purine Anatgonists (Analogue) 6-Meracaptopurine Fludarabine Pyrimidine Antagonists (Analogues) 5-Fluorouracil Gemcitabine Cytarabine
Cytotoxic Antibiotics
Anthracyclines Doxorubicin Daunorubicin Idarubicin Epirubicin Glycopeptides Bleomycin Dactinomycin Mitomycin
Plant Derivatives (Microtubule inhibitors)
Vinca Alkaloids (Vinca Rosa) Vincristine Vinblastine Vinflunine Vinorelbine Taxols Paclitaxel Docetaxel Cabazitaxel
General Side effects of Anticancer drugs Side effects greatest in rapidly-dividing cells
• Bone marrow suppression (myelosupression)
• Impaired wound healing • Hair follicle damage - alopecia • GI epithelium damage • Growth retardation in children • Damages gametes leading to sterility • Fetus - teratogenicity
(note: the drugs are also carcinogenic) !
Alkylating Agents - group of drugs that bind covalently to nucleophilds – which causes the formation of cross-linking - affects the cells in the S phase (DNA synthesis phase) Cyclophosphamide (a nitrogen mustard) - most common drug - it is a prodrug that is then metabolized by the liver - effects lymphocytes (therefore it is a immunosuppressant) - can be used Oral or IV:
• Acute/chronic lymphocyte leukemia • Non-Hodgkin lymphoma • Breast, lung and ovarian cancers
- Adverse effects: • Nausea and vomting • !Bone marrow depression – treated with Amifostine • Reduced fertibility • !Haemorrhagic cystitis – treated with MESNA
o cyclophosphamide causes the formation of acrolein (which is cytotoxic), Mesna inhibits the acrolein Ntirosoureas - Mech. Of Action: alkylate DNA - !Used to treat brain tumors (meningeal tumours) - !Carmustine causes pulmonary fibrosis Busulfan - selective on bone marrow " used on chronic granulocytic leukemia
• (but now the 2nd drug of choice because of its adverse effects) - Low dose: depresses the granulocytes and platelet formation - High dose: depresses red blood cell formation - causes pulmonary fibrosis (bulsuphan and carmustine) Cisplatin (of platinum compounds) - analogoues of alkylating agents - used on solid tumours of testes and ovary (administered by IV) - !Adverse effects:
• Nephrotoxicity • Severe nausea and vomiting – treated with 5-HT3 anatoginsts (refer to notes from antiemetic drugs - week 10) • Ototoxicity (ranges from tinnitus to hearing loss) • Neuropathy • Myelosupression (bone marrow suppression)
Antimetabolites - this group of drugs mimic the structures of metabolic molecules - affects cells in the S phase !Methotrexate - Folic Acid Analogues - folic acid is essential in the synthesis of purine
- Methotrexate binds to dihydrofolic acid reductase (it has a higher affinity for the enzyme than FH2) !- Its function in relation to Folic Acid include:
• Inhibits DHFR (direct effect) • Inhibits oxidation of FH2 to FH4 (caused by DHFR inhibition) • Inhibits Purine and Pyrine synthesis (downstream) • Inhibits DNA&RNA synthesis (downstreadm)
- It is used to treat: *contraindicated in pregnancy
• !Autoimmune diseases (Rheumatoid arthritis, psoriasis, crohn disease) – very useful, as methotrexate suppresses the immune system
• Lymphocytic leukemia • Choriocarcinoas • Breast cancer • Head and neck carcinomas
- Adverse Effects
• N/V/D • Stomatitis (cold sores) • !Severe mucositis – at very high doses • Erythema • Alopecia • !Pulmonary toxicity • !Neurologiy toxicities
!Leucovorin and Folic Acid - adverse effects (hepatotoxicity) can be minimized or avoided with the use of leucovorin/Folic Acid - Leucovorin and Folic Acid is given together with Methotrexate in Autoimmune diseases (i.e. rheumatoid arthritis) " to prevent adverse effects i.e. severe mucositis - F.A & Leucovorin is not given, when treating cancers as it interfers with therapeutic effects
• When given – it is at a minimal dose
5-Fluorouracil – Pyrimidine Analogues - inhibits the enzyme thymidylate synthetase
• This block dTMP synthesis which is required for DNA synthesis and cell growth - administered route:
• IV • Topically – for skin cancer • NOT ORALLY – highly toxic to the GI tract
- Use: • It is the drug of choice for slow growing cancers
o E.g. superficial basal cell carcinomas (skin cancer), breast, ovarian and gastric carcinomas • Cisplatin (platinum compound) + Fluorouracil in combno " used in conjunction with Radiotherapy for
head&neck cancer - Adverse effects
• N/V/D • Alopecia • Severe ulceration of oral and GI mucosa • Anorexia
- note: Gemcitabine has fewer adverse effects 6-Mercaptopurine – Purine Analogues
- 6-MP (6-mercaptopurine) is converted to 6-TIMP, which has the anti-cancer effect - !6-MP, Allopurine and Azathiopurine CANNOT be taken together # they cause dray interactions
• !Note: Allopurine is a drug for gout
Cytotoxic Antibiotics Doxorubicin - Mech of Action: metabolized by CYP enzyme producing free radicals
• The free radicals attacks DNA strands breaking them – which inhibits DNA replication - Adverse effects
• Although the free radicals attacks DNA strands of tumour cells • It also damage normal cells – the free radical causes oxidative membrane damage " causing Cardiotoxicity • Bone marrow suppression • Alopecia
Bleomycin - also generates free radicals and degrades DNA - causes pulmonary fibrosis
Plant Derivatives - acts during mitosis of cells (during metaphase) - it inhibits micro-tubular activity and spindle formation - it is relatively non-toxic
Week 10 – Antihistamines and GI Drugs
- Histamine is synthesized, stored and released in: 1. mast cells: found in the skin, GI tract and the respiratory tract, 2. basophils: found in the blood 3. neurons: in the CNS and peripheral neural system (PNS)
- histamine is metabolized by the P450 system - there are 4 different types of histamine receptors H1 coupled to Phospholipase C (PLC); ↑IP3 & DAG Smooth muscle, endothelial cells, CNS H2 coupled to Adenylyl Cyclase (AC); ↑cAMP GI parietal cells, vascular smooth muscle cells, cardiac
cells - the pharmacological effects of the receptors on the different systems are include:
System Structure Receptor Effect CVS Capillary H1 and H2 • Dilation
• increased permeability Arteriole (smooth muscle) H1 and H2 • Dilation
• decrease in blood pressure • increase heart rate • positive inotropic (contractility) and chronotropic
effects Respiratory Bronchio-smooth muscles H1 • Contraction
• Asthma symptoms • Decrease in lung capacity
GIT Gastrointestinal smooth muscles
H1 • Contraction • Intestinal cramps • Diarrhea
Parietal Cells H2 • Increase gastric acid secretion Exocrine Adrenal medulla H1 • Adrenaline and noradrenaline release
Epidermis H1 • Triple Response of Lewis (flush, flare, wheal) Neural Nerve endings H1 • Pain
• Itch CAN H1 • Motion sickness
• Sedative effect - Pathophysiological effects of histamine, histamine causes:
• Allergic reactions o Type I hypersensitivity reactions, such as:
! urtericaria; ! angioedema;
! bronchoconstriction; ! anaphylactic reaction
• Inflammation • Wakefulness (as a neurotransmitter)
H1 receptor blockers (antihistamines)
1st Generation 2nd Generation Alkylamines
• Chlorpheniramine • Brompheniramine • Dexchlorpheniramine • Pheniramine
Ethanolamines • Diphenhydramine • Dimenhydrinate • Doxylamine
Phenothiazine • Promethazine • Trimeprazine
Piperazines • Cyclizine • Meclizine
- these have a less sedating effect (compared to 1st gen) • Cetrizine • Levocetrizine • Fexofenadine • Loratadine • Desloratadine
- Receptors that are blocked by H1-antihistamines and effects caused include:
• Cholinergic Receptors o Increases dry mouth o Increase urinary rention o Increase tachycardia
• Alpha-adrenergic Receptors o Increase hypotension o Increase dizziness o Increase tachycardia
• Serotonin o Increases appetite
• H1 Histamine Receptors o Sedation o Decreases inflammation, itching,
sneezing o Antinausea and antiemetic effect by
decreasing neurotransmission in the CNS
- Adverse effects caused by H1-antihistamines are:
• Drowsiness • Urinary rentension • Tachycardia • Hypotension • Vertigo (nausea) • Dry mouth • Increased appetite • Blurred vision • constipation
- drugs that interact with antihistamines and enhances the effects of antihistamines include:
• classical antimuscarinics • potential CNS depressants
o opiods o sedatives o general and narcotic analgesics o alcohols
- 2nd Generation antihistamine drugs
• they have a much lower incidence of adverse effects than the first generation drugs • Erythromycin and ketoconazole inhibit the metabolism of fexofenadine and loratadine in healthy subjects • Fexofenadine and loratadine have a lower potential to induce drowsiness
- Therapeutic uses of Antihistamine Drugs
• Antiallergies – ALL antihistamine drugs • Sedative effects to treat insomnia – Diphenhydramine, Doxylamine • Prevent motion sickness – Meclizine, cyclizine • Antiemetic (prevent vomiting) – promethazine • Local anesthetic – diphenhydramine
Antiemetic drugs (vomiting prevention) Anti-cholinergic • Scopolamine (L-hyoscine) Anti-histamine • Cinnarizine
• Cyclizine • Promethazine
Dopamine antagonist • Metoclopramide • Domperidone • Droperidol • Haloperidol
Corticosteroid • Dexamethasone Histamine analogue • Betahistine 5-HT3 (Serotonin) Blockers/Antagonists • Granisetron
• Ondansetron – very fast oral absorption • Tropisetron • Palonosetron
- Properties and mechanism of Metoclopramide and Domperidone
• They are both D2-receptor antagonists (dopamine receptor) • They act on the chemoreceptor trigger zone • Metoclopramide at higher doses act on 5-HT3 receptor anatagonists • Mainly used for drug and surgery induced vomiting
-Effects of Metoclopramide and Domperidone:
• Increase in gastro-oesophageal sphincter tone • Increase in gastric emptying • Increase in small intestine motility • Domperidone – has no effect on the CNS • Metoclopramide - produces CNS side effects
- Adverse effects of Metoclopramide and Domperidone • Dystonia (sustained abnormal muscle contractions) • Akathesia (inner restlessness) • Parkinsonian-like syndromes • Hyperprolactinemia • Drowsiness – metoclopramide only
- Properties and mechanism of 5HT3 receptor antagonists • Block 5HT3 receptors in the CTZ and the guts • The different routes that it can be given include – intravenous, intramuscular injection, suppository • They are usually given before chemotherapy
- Adverse effects of 5HT3 receptor antagonists include:
• headache - common • constipation - caused by 5HT3 receptor blockade in the gut • flushing • hiccups
Inhibition or Neutralisation of Gastric acid secretion - the 3 groups of drugs that can inhibit or neutralize gastric acid secretion include: 1. H2 recetpor blockers 2. Proton pump inhibitors 3. anatacids H2 Receptor Antagonists
• Cimetidine • Ranitidine • Famotidine • Nizatidine
Proton-pump inhibitors • Omeprazole • Lansoprazole • Pantoprazole • Rabeprazole • Esmoprazole
Antacids • Aluminium hydroxide • Calcium carbonate • Magnesium hydroxide • Sodium bicarbonate • Alginates
H2 Receptor Antagonists - properties and mechanism of H2 Receptor Anatognists:
• competitively inhibit the histamine H2-receptors on the gastric parietal cells • Well absorbed orally • Undergo limited first pass • the half-life of most of H2 blockers is only 2-3 hours, therefore administered once or twice daily • clinically uses include: peptide ulcers, gastro-esophageal reflux disease, reflux oesophagitis
-Effects of H2 Receptor Antagonists include:
• Inhibits gastrin and acetylcholine stimulated acid secretion
• Reduce basal acid secretion and pepsin production • inhibit the increase in secretion that occurs in
response to various stimuli
- Adverse Effects of H2 Receptor Antagonists include: • Diarrhoea, and other gastrointestinal disturbances • Dizziness, headache • Confusion in elderly • Cimetidine, itself causes:
1. Antiandrogenic effects – leading to gyanecomastia & impotency
2. Inhibition of metabolic CYP enzymes 3. Increasing interactions with other drugs,
therefore drug doses need to be reduced when patients are taking cimetidine
Proton Pump Inhibitors (PPIs) - properties and mechanism of PPIs:
• Irreversible inhibition of H+/K+ - ATPase o Note: H/K ATPAse is the proton pump o The return of acid secretion is dependent on the synthesis of new proton pumps
• Clinical uses of PPIs include: o Peptic Ulcers o Reflux oesophagitis o Component of H Pylori eradication
! To eradicate H.pylori a PPI is given together with clarithromycin and amoxycillin - Effects of PPIs
• Decreases gastric acid secretion of parietal cells - Adverse Effects of PPIs:
• Gastrointestinal upset – abdominal pain, nausea, vomiting, diarrhoea
• Headache • Hypersensitivity reactions – skin rashes, urticaria,
angioedema and anaphylaxis • Oedema • Muscle and joint pain • Blurred vision and dry mouth
- Specific Properties of Omeprazole
• It is a weak base • It is a prodrug (a drug that is administered in a fully or partially inactive form)
o It has to be first protonated to become an active drug • It Is given as a enteric-coated formulation
Antacids - Effects of Antacids
• Antacids neutralises the gastric acid and thus raise the gastric pH
• Produce a quick relief in peptic ulcer symptoms, large doses required to heal the ulcers
- Adverse Effects of Antacids include: • Constipation with aluminium salts • diarrhoea with magnesium salts
- Properties of Antacids:
• Magnesium salts neutralise acid more rapidly than aluminium salts • They have a more prolonged effect if taken after food • Without food, effects does not last more than an hour (as gastric emptying occurs) • Produces a quick relief in peptic ulcer symptoms
o Larger doses are required to heal the ulcers • Clinical uses include:
o Dyspepsia o Symptomatic relief of peptic ulcers o Oesophagel reflux
Cytoprotective drugs - Cytoprotective drugs include: Sucralfate, Bismuth Salts, Misoprostol - The drug creates a protective barrier between ulcer and acidic environment - it inhibits diffusion of gastric acid Sulcralfate
• Stimulates the gastric secretion of bicarbonate and prostaglandins
• Adverse effects include: constipation, diarrhea, dry mouth, nausea
Bismuth Salts • Used in conjunction with
antibiotics given for H.Pylori induced ulcers
• Adverse effects: blackened stools, darkened tongue, staining of teeth
Misoprostol • Increase gastric mucus
production • Increases duodenal
bicarbonate secretion • Inhibition of gastric acid
secretion • Mostly used to reduce NSAID-
induced gastric damage
