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%
%

1!

*Injection%!this!can!include:!subcutaneous,!intramuscular,!intravenous!
%
Advantages%
Disadvantages%
Intramuscular%
#!can!be!given!in!a!slow!and!sustained!
#!can!be!painful!
%
way!
#!can!lead!to!muscular!distrophy!
!

Subcutaneous%

Intravenous%
%

#!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!

#!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/

2!

#!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!
!

3!

#!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!pkinetics!when!two!drugs!are!pharmaceutically!equivalent!
such!that!the!drugs!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%

4!

#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!

5!

#!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!Johns!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!
!
!

6!

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!produce3physiological3and3
biochemical3effects!
!
"!in!simpler!terms,!when!a!drug!binds!to!a!receptor!a!pharmacological0effect!is!produced!
!
*(e.g.!adrenaline!binds!to!"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!produce3a3
pharmacological3response3
3
*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
"!a!drug!which!binds!to!the!
receptor!and!produces!a!
pharmacological!effect!
100%!affinity!!
100%!efficacy!

!
Partial3Agonist3
"!has!affinity!for!receptor!
"!but!lower0efficacy!compared!to!
another!agonist!acting!at!the!same!
receptor!
100%!affinity!
50%!efficacy!

Antagonist3
"!a!drug!which!competes!and!
binds!to!the!same!receptor!
"!but!does!NOT!activate!the!
receptor!
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!inactive0
state!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!
Emax3of3the3agonists3becomes3depressed3(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,!the3
response3will3increase3in3proportion3to3the3dose3until3all3the3
receptors3are3occupied3(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:!
*Emax33this!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!
*KA33refers!to!the!concentration3of3a3drug!that!has!occupied!50%!of!the!total!number!of!
receptors!at!equilibrium.!This!is!the!dissocitation0constant.!The3LOWER3the3value,3the3HIGHER3
the3affinity3the3drug3has3to3the3receptor3
!
!
!
!

"!Hypobolic3(arithmetic)3vs3Sigmoid3(log3scale)3
Hypobolic3
3
T3this!type!of!graph!is!
difficult!to!analyse!
mathematically!

LogTscale!

3
T3allows!the!illustration!
of!proportionate!doses!
at!equal!intervals!
"!straighter!lines!
"!easier!to!analyse!
mathematically!
3

%!maximal!response!

3
T3Drug3efficacy3vs3drug3potency3
"!the!Emax!value!determines!the!drug0effectiveness!
!
!
*the!Emax!value!refers!to!the!drugs!maximal0efficacy0
!
*the!drugs!effectiveness!has!nothing!to!do!with!the!drugs!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!
!
!
!
!
Concentration!
!
"!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!

"!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!compete0
for!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!inactive0
receptors!!
"!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)3
Antagonism3
Pharmacokinetic3
antagonism3
Chemical3
antagonism!
Noncompetitive3
antagonism!

"!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!
"!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!
"!chemical!antagonist!combines!with!other!drugs!to!produce!insoluble,!inactive!
complexed!
"!example:!protamine!sulphate!neutralising!the!action!of!heparin!
!"!this!is!when!the!antagonist!doesnt!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:"
Tyrosine

Tyrosine)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"
*9adrenoreceptor"!"inhibited"by-9
adrenoreceptor-antagonist*-29adrenoreceptor-!""
!"stimulated"by"29agonists!"inhibited"by"29antagonists*9adrenoreceptors"!"inhibited"by"9
adrenoreceptorAdrenoceptor-Drugs--Agonist-and-Antagonist!"the"main"Adrenoceptor-Agonists"include:"
Direct-ActingNon9selective-Agonists9receptor-agonists"
(activates-both--and-)!"noradrenaline"
19selective!"adrenaline"
!phenylephrine"
!"isoproterenol"
29selective!"dobutamine"(1)"
!clonidine"

Indirect-Acting!"Amphetamine"
!"Tyramine"
!Ephedrine"
!"cocaine"
"

29receptor-agonists-

(these"are""2"inhaled"agonists)"

Short-Acting!salbutamol"
!terbutaline"
Long-Acting-(12hours)!salmeterol"
!eformoterol"
!"indacaterol"

"
!"the"main"Adrenoceptor-Antagonists"include:"
Non9selective-Antagonists(activates-both--and-)-

!"labetalol""
!"carvediolol"

9receptor-anatgonists"

9receptor-antagonists-

Non9selective!phenozybenzamine"
!"phentolamine"
19selective!"prazosin"
!"terazosin"

Non9selective!"propranolol"
!pindolol"
!"oxprenolol"
19selective"

!"atenolol"
!"bisoprolol"
!metoprolol"
!nebivolol"

"

Adrenergic-Receptors"
!"also"known"as"adrenoceptors"
!"there"are"2"main"types"of"adrenergic"receptors:"
"
*--receptors*--receptors"
!"ALL"adrenergic"receptors"are"""g"protein*coupled*receptors"
"
Agonist-potency"
!"the"agonist-potency"when"the"receptors"are"stimulated"by"agonists"are"as"follows:"
NA:"1-=-2,--1->-2"
"
*""="noradrenaline">"adrenaline">isoprotenernol"
Adren:"1-=-2,-1-=-2"
"
[note:"this"means"that"noradrenaline"causes"the"strongest"effect]"
Isopro:"1-=-2->>-"
"
*"="isoprotenernol">"adrenaline">"noradreanline"
"
[-Receptors]9"there"are"2"main"!receptors"subtypes,"which"are:"
"
*"1-="Gq-receptor*-2-=-Gi-receptor"
General-LocationMechanism/ActionEffects/Response1" Smooth"muscles"
Gq"!"activation"of"PLC"
!"vasoconstriction"(causing"increase"in"BP)"
(including"blood"
!"hence"increasing"[Ca2+]"
!"GI"tract"smooth"muscle"relaxation"
vessels)"
!"salivary"secretion"
!"glycogenolysis"
2" !"Parasympathetic"
Gi"!"inhibition"of"AC"
!"inhibition"of"NT"release"(NA,"ACh)"!"
presynaptic"
!"hence"decrease"in"[Ca2+]" responsible"for"feedback"control"of"NA"release"
receptors"
!"inhibition"of"insulin"release"
!"platelets"
!"platelet"aggregation"
"
!"2-receptors"are"also"responsible"for"the"negative-feed-back"of"NA-release"
"
!"after,"NA"is"released"it:"
1."binds"to"2-receptors"which"then"inhibits"adenylate-cyclase"and"
prevents"it"from"causing"further"release"of"NA"
2."binds"to"postsynaptic"receptors"
"
"
[-Receptors]"
!"there"are"3"subtypes"of"!receptors:"1,-2-and-3"
"
*they"are"ALL"Gs9receptors"
"
General-LocationMechanism/ActionEffects/Response1" Heart"
!"+ve"inotropic"effect"(force"of"contraction)"
!"+ve"chronotropic"effect"(HR)"
!"+ve"dromotropic"effect"(conduction"speed"of"
AV"node)"
2" !"Lungs"
!"bronchodilation"
Gs"!"stimulation"of"AC"
!"Smooth"muscles"
!"vasodilation"
!"hence"increase"in"[Ca2+]"
!"visceral"smooth"muscle"relaxation"
and"stimulation"PKA"
!"glycogenolysis"
!"muscle-tremors""
!"decrease"in"intraocular"pressure"
3- !"Adipose"tissue"
!"lipolysis"
(metabolism)"
!"note:"stimulation"of"the"2-receptor"reduces"histamine"release"!"which"is"used"to"treat"anaphylactic"
reactions"

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"
!asthma"
29receptor-agonists-

"

(i.e."salbutamol,"terbutaline,"
salmeterol,"eformoterol)"

*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--Adrenoceptor-Antagonists9-the"uses"of"the"-antagonists-include:"
Phentolamine!"decrease"in"total"peripheral"resistance"
!"decrease"in"blood"pressure"
!"increase"in"cardiac"output"and"heart"rate"
!"can"cause"postural*hypotension*
19selective-antagonists!vasodilation"
(Prazosin,"Terazosin)"
!"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"-antagonists"include:"
"
*postural"hypotension"
"
*vertigo"(dizziness)"
"
*tachycardia"
"
Clinical-Uses-and-adverse-effects-of--Adrenoceptor-Antagonists!"the"clinical"uses"of"-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)"
"
MAO

"

Aldehyde'
dehydrogenase

catecholamines,
!Aldehydes!
!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""and"-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,! ,,and,,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,"
Skeletal"muscle"contraction"
increases"cation"
Nn,
Autonomic"ganglia"
!"catecholamine"secretion"
(Na+"and"K+)"
!"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"
Neuromodulation"of"NT"
!"eventually"causing"depolarization"
and"excitation"
M2, Cardiac"
Gi"!"inhibition"of"AC"
F,cardiac"inhibition""
!"causing"decrease"in"cAMP"and"
*decrease"HR"
hence"decrease"in"[Ca2+]"
*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,
Muscarinic,Receptor,
Acetylcholine,
Neuromuscular,
Agonists,
(competitive),Antagonists, Esterase,inhibitors*,
Junction,Blockers,
!"acetylcholine"
1Atropine'
Reversible,
NonFdepolarising,
!"pilocarpine"
!"Scopolamine"
FEdrophonium""
F,mivacuroium"
!"muscarine"
!"Ipratropium(
!"Neostigmine"
!"vecuroium"
!"bethanechol"
1Darifenacin'
!Physostigmine"
!"atracuroium"
1carbachol'
!Tropicamide"
!Pyridostigmine"
!"ciscuroium""
!"Cyclopentolate"
!,Rivastigmine"
!pancuroium"
!Galantamine"
!rocuroium'
!Donepezil"
Depolarising,
Irreversible,
FSuccinylcholine"
F,ecothiophate,
"(also"known"as"
!"organophsophate"
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,
!"short"acting:"2!"10min"
!longer"acting:"0.5"to"6"
!"used"as"a"diagnostic"drug"
hours"
!"test"for"Myasthenia"gravis"(an"
!"used"to"treat"Myasthenia"
autoimmune"disorder"where"ACh"
gravis"
receptors"are"destroyed"by"antibodies)"
!"causes"muscle"weakness"
"

Rivastigmine,
Galatamine,
Donepezil,
!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,, !"DUMBELS"
synapses,
!"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:"Pdynamic)"
"
!"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"
Mivacurium"
Vecuronium"
pancuronium"
onset""1"min)"
Atracurium"
"!!"note:"this"is"a"
Cis!atracurium"
DEPOLARISING"blocker"
"
[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:!
!
*!13adrenoceptors*!!!regulates!the!heart!(especially!the!contractility!of!the!heart)!
!
**13*adrenoceptors*!!regulates!the!blood*vessels*(especially!the!vasoconstriction!of!vessels)!
!
[Renin3angiotensin3aldosterone*system]!

!
Antihypertensive*Drugs!
"!the!different!antihypertensive!drugs!that!are!available!include:!
!
*!"adrenoceptor!antagonists!
!
*!"adrenoceptor!antagonists!
Note:!
!
*centrally!acting!(2"agonists) anti"hypertensives!
"!!the!first!choice!drug!for!
!
*drugs!directly!affecting!the!RAAS!
hypertension!is!usually!B3blockers!
!
!
"!ACE!inhibitors!
"!for!milder!hypertension!cases!
!
!
"!Ang"II!receptor!antagonists!
diuretics!are!usually!used!
!
*Other!vasodilators!!
"!nitrovasodilators,!calcium!channel!blockers,!potassium!channel!blockers,!diuretics!

3adrenoceptor*antagonists*
Non3selective*Antagonists*
(activates*both**and*)*

"!labetalol!!
"!carvediolol!

Nonselective*3receptor*
anatgonists!
"!propranolol!
"pindolol!
"!oxprenolol!
!

!
"!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*
*angina!pectoris!
*bradycardia!
*myocardial!infarction!
*hypoglycaemia!
*heart!failure!
*fatigue!
*hypertension!
*reduced!libido!
*glaucoma!(timolol*
*drug!withdrawal!(when!drug!is!
eyedrops)!
stopped!suddenly,!it!can!cause!angina)!
*anxiety!control!
*DONT!USE!in!asthmatic!patients!
*arrhythmias!
*

13receptor*selective*antagonists*

"!atenolol!
"!bisoprolol!
"metoprolol!
"nebivolol!

DENTAL*IMPLICATIONS*
*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)!

3Adrenoceptor*Antagonists*
Non3selective*Antagonists*
(activates*both**and*)*

A13receptor*selective*antagonists*

"!labetalol!!
"!carvediolol!
!
CLINICAL*USES*
"!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!
!

"!prazosin!
"terazosin!
"doxazosin!
ADVERSE*EFFECTS*
*postural!hypotension!!
*headache,!dizziness!
*nausea!
*incontinence!

DENTAL*IMPLICATIONS*
"!reverses!the!effect!of!adrenaline!

Centrally*Acting*(23agonists) Anti3hypertensives!
"!the!true!Centrally!Acting!23agonists!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!
"candesartan!
"!lisinopril!
"losartan!
"ramipril!
"valsartan!
"enalapril!
"telmisartan!
"fosinopril!
"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!persistent!dry!cough!(caused!by!bradykinin)*
3*treatment!of!heart*failure*
3*angioedema!
3*prevention!of!secondary*myocardial*infarction!
"!disturbances!of!taste,!nausea,!vomiting!
"!treats!insulin3dependent*diabetes*
"!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!dont!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:!
Non3dihydropyridines*(non3DHP)*
Dihydropyridines*(DHP)*
"amlodipine!
"verapamil!
"felodipine!
"!diltiazem!
"nifedipine!
"minodipine!
!
!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!
3*non3DHP*=!inhibits!metabolism!
"!nifedipine!or!amlodipine!=!hypertension!
"!the!effects!of!CCBs*are!NOT*REDUCED!by!the!use!of!
"!diltiazem!or!other*DHP!=!angina!prevention! 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*
Loop*Diuretics**
"!frusemide!
"!oedema!
(blocks!the!reabsorption! "!bumetanide!
"!hypertension!
of!sodium)!
"!ethacrynic!acid!
"!acute!hypercalcaeia!
Thiazides!(inhibits!
sodium"chloride!
symporter!of!the!distal*
tubule)!
Potassium3sparing*
diuretics!
(inhibits!sodium"
chloride!symporter!of!
the!collecting!tubules,!K+!
channels!not!affected)*
Carbonic*Anhydrase!
(proximal!tubule)!

Unwanted*Effects*
"!hypovolemia!(excessive!
loss!of!platelets)!
"!hypokalemia!(potassium)!
"!hypomagnesemia!
"!hyperuricemia!
"!hypokalemia!
"!hyperuricaemia!
!

"hydrochlorothiazide*
"!chlorthalidone!
"!indapamide!

"!hypertension!
"mild!heart!failure!
"!severe!oedema!

"!spironolactone*
"!amiloride!

"!used!together!with!
thiazide!diuretics!
"!prevents!
hypokalemia!
"!heart!failure!

"!acetazolamide!
"!dorzolamide!
"!brinzolamide!

"!reduces!intra"ocular! !
pressure!in!open"
angle!glaucoma!

"!hyperkalemia!
"!GI!tract!disturbances!
"!causes!androgen!like!
effects!

!
"!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*
"!stable!angina!(prevention!
using!sublingual)!
"!unstable!angina!(IV)!
"!acute!heart!failure!(IV)!

ADVERSE*EFFECTS*
"!venodilation!!!causing!postural!
hypotension,!headaches!
"!arterial!dilation!
"!tolerance!
"!drug!interactions!(when!2!types!of!
vasodilatory!drugs!are!combined)!

DENTAL*IMPLICATIONS*
"!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!
!
"!the!mechanism/action*!of!digoxin!is!as!follows:!

!
*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)!

ADVERSE*EFFECTS*
"!cardiac!arrhythmias!(caused!by!calcium!
increase)!
"!increase!vagal!tone!!!blocking!AV!node!
"!GI!tract!disturbances!causing!vomiting,!
nausea!etc!
"!neurological!disturbances!(i.e.!fatigue)!
*
!
!
!
!
!

DENTAL*IMPLICATIONS*
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)! Ia!!disopyramide!
*slow!down!depolarization!
Ib**lignocaine!!
Ic!!flecainide!
II!
Beta3blocking*agents*
Propranolol!
*affects!contractility!
Esmolol!
Sotalol!
Metoprolol!
III!
Potassium*Channel*Blockers*
Amiodarone!
*widen!the!action!potential!
Sotalol!
IV!
Calcium*channel*blockers!
Verapamil!
*slows!down!conduction!
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!
"!inactivates!clotting!factors!
"!prevents!venous!thrombosis!
"!anticoagulant!
Warfarin!
"!decreases!clotting!factor!synthesis!
"!prevents!venous!thrombosis!
"!anticoagulant,!oral!
Aspirin!
"!decrease!platelet!aggregation!
"!prevent!arterial!thrombosis!
"!antiplatelet!drugs!
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)!
!
"!warafins!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!
*Rosuvastatin!
!
*Fluvastatin!
*Simvastatin!
!
*Pravastatin!
!
" refer!to!notes!for!mechanism*
!
CLINICAL*USES*
ADVERSE*EFFECTS*
"!hypercholesterolemia*
3*GI!tract!upset!(nausea,!vomiting,!diarrhoea)!
3high!risk!of!coronary!artery!disease!
"!dizziness,!headache!
"!mixed!hyperlipidemia!
"!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&
Lidocaine/Lignocaine!
Cocaine&!
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:!
Blocked!first!
Non"myelinated!
Small!type!C!fibres!
Dull!pain!
!
!
Type!A!
Sharp!pain!+!Temp!
!
!
Type!A!
Touch/pressure!
!
Blocked!last!
Highly!myelinated!
Type!A!
Motor!
!
!

Order&of&Sensory&function&block&
&

Sensory!function!Recovery!

Toxicities&of&Local&Anaesthetics!
" Local!toxicity!can!be!caused!by:!
o Epithelial!tissue!damage!
o Nerve!tissue!damage!
o Vascular!(systemic)!damage!
!
!
!

"!pain!
"!cold!
"!warmth!
"!touch!
"!deep!pressure!
"!motor!
!

Sensory!function!loss!

"!the!effects!caused!by!the!different!tissue!damages!include:!
Epithelial&Tissue&Damage&
Nerve&tissue&damage&
<&tissue!edema!(swelling)!
<&anaesthesia!(unconsciousness)!
"desquamation!
"!paresthesia!(tingly!sensation)!
"!necrosis!
"!decrease!in!wound!healing!

Systemic&Damage&
"!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!
<&increase!risk!of!local!tissue!injury!and!tissue!
"!decrease!in!dose!of!LA!needed!
necrosis!
"!decrease!risk!of!bleeding!
"!delay!in!wound!healing!
"!increase!intensity!of!nerve!block!
"!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
- No Allergy
- Can orally
- No allergy
- Cannot oral
- Allergy to penicillin
- Can oral
- Allergy to penicillin
- Cannot oral

Drug
Amoxycillin OR
Ampicillin
Amoxycillin OR
Ampicillin

Dose

Route

Time

2g

Oral

1 hr before procedure

2g

IV/IM

IV 30 mins before
IM just prior

Clindamycin

600 mg

Oral

1 hr before

IV

Clindamycin 20
mins infusion prior to
procedure
Lincomycin 1hr
infusion prior to
procedure

Clindamycin OR
Lincomycin

600 mg

Antibiotic Therapy
Amoxycillin
Phenoxymethylpenicillin
Clindamycin
Metronidazole

x500mg
x500mg
x300mg
x400mg

x5hr
x6hr
x8hr
x12hr

x5days
x5days
x5days
x5days

For unresponsive/severe infections

Metronidazole
x400mg
PLUS EITHER
Phenoxymethylpenicillin
x500mg
Amoxycillin
x500mg
Amoxycillin + Clavulanic Acid x875mg+185mg

- as sub for patients allergic to penicillin

x12hr

x5days

x6hr
x8hr
x12hr

x5days
x5days
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:
Lymes 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

Terbinafine
Caspofungin
Flucytosine

Triazoles - Applied Topic OR Sym

Fluconazole
Itraconazole
Posaconazole
Voriconazole
Ketoconazole not sym/oral

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

Severe primary episodes

5% cream topically

Penciclovir

1% cream topically

Aciclovir
Valaciclovir

400mg orally
1g

x5 times/day
OR every 4 hours
x6 times/day
OR every 2 hours
x5 times/day
z12hr

x4 days
x4 days
x7days
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

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)

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

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
!Leucovorin and Folic Acid
Breast cancer
- adverse effects (hepatotoxicity) can be minimized
Head and neck carcinomas
or avoided with the use of leucovorin/Folic Acid
- Adverse Effects
N/V/D
Stomatitis (cold sores)
!Severe mucositis at very high doses
Erythema
Alopecia
!Pulmonary toxicity
!Neurologiy toxicities

- 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
H2 coupled to Adenylyl Cyclase (AC); cAMP

Smooth muscle, endothelial cells, CNS

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
H1
Contraction
muscles
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;
! bronchoconstriction;
! angioedema;
! anaphylactic reaction
Inflammation
Wakefulness (as a neurotransmitter)
H1 receptor blockers (antihistamines)
1st Generation
Alkylamines
Phenothiazine
Chlorpheniramine
Promethazine
Brompheniramine
Trimeprazine
Piperazines
Dexchlorpheniramine
Cyclizine
Pheniramine
Ethanolamines
Meclizine
Diphenhydramine
Dimenhydrinate
Doxylamine

2nd Generation
- 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
Anti-histamine
Dopamine antagonist

Corticosteroid
Histamine analogue
5-HT3 (Serotonin) Blockers/Antagonists

Scopolamine (L-hyoscine)
Cinnarizine
Cyclizine
Promethazine
Metoclopramide
Domperidone
Droperidol
Haloperidol
Dexamethasone
Betahistine
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 NSAIDinduced gastric damage