It is more blessed to give than to receive

'It is more blessed to give than to receive.
GEN ERA L PH A RM A COLO G Y

Yzz/r/#zzc//yp toPharmactjlogy)
sphartnàcilogy:
lsthe sçience which deals w ith drugs.
*Drugs:
*rfhesearcchcmicalagentsusedfor:tregtlnent(cure)()17diseases,
prophvlakts(prevention)ofdiseasesasl-tkllnpicin in llrophylaxisagainst
meningitis,aspirin in prophylaxisagainstthrolnbo-enlbolism,and
nitrates in prophylaxis againstangina pectoris-diagnosisofdiseasesas
radioactiyeiodine(1132)indiagnosisol'tllyroid
' )
l'
-tlnctions--andfor
prevention ofpregnancy (contraceptioq). .
*'
D rugs ''m odffy''an existing cellfunction eitherby stilnulation
(activation)orinhibition(depression)buttlleydollotcreateanew
ftlnction. '
*'
Names(Nomenclature)ofdrugs:
1-Chem icalnam e.
2-N on-propietary= Generic name(may bereferred to asscientifie
nam el.
3-Propietary= Comm ercialnafne(may bef'efkrrettG astraddname).
*lklostdfugs are purchased only accordillg to a ''prescription''and are
ltnow n as''Prescrlvtion-onlv tnedication = PO 54''w hereas few drugsare
purchased withoutaprescription asantipyretics(aspirin alld ,
paracetafnol),drugsforcommonc01d,and laxativestlsed intreatnzentof
constipation.These drugsare know n as ''
O ver '
/>t?(L
lottnter t
W '//g,j'=u
/3///-
1/-$.to l/.çc(flw aboutlr/g,îis
.. .
'
4'
-hemelz'
-. .
1-Sottrce. '
11-C/v zzpj-s-//'y'
.
111-Pharm acokinetics.
/Pt Pharmacodynam ics.
IQ lndications = Therapeutic ttses.
V1-yltA/e/w: effects.
. .
*e*
Iz11-C'
-
'tn/-
?/rti
/jzltF
/jctr//jtvil.
V111-D?-z/, g'Interactions.
1X-Routes tl -/-x-
rlt7
///'
/ïnj-
s'//'l/j/n.
l
WhiteKnightLove
Freely you have received; freely give.
1-sbt/rce-
l1ofDrugs:
l-plantsouices:e.g.Atropine isobtained t'
rom Atropabelladùnnaand
otherplants,M orphine isbbtained from Papaversom niferum ,Ephedrine
is obtained from Ephedra plant,etc...
z-Animal'sources:e.g.animallnsulinwaspreparedfrom pigs(knownas
porcineinsulin)andfrom cattle(knownasbovineinsulin),Heparin
(unfractipnatedheparin= UFH)isobtainedfrom thelungsand intestines
ofcattleand pigs.These drtlgsare highly antigenic and are replaced ntlw
by human insulin and low molecularweightheparins(I-M W Hs);
respectively.
3-M icroorganisms'
.Antibiotics(aspenicillin t'
J'
)areprepared from
m icroorganism sasfungiand bacteria.
p-M ineralsources'
.e.g.iodineand magnesiutn sltlphate,and also
radioactiveisotopesas1131(therapetltic)and1132(diagnostic).
s-svntheiicdrugs'.m ostdrugsarechenlically synthesized,e.g.Aspirtn,
Propranolol,Sulphonam ides:Benzodiazepines,Paracetamol,etc...
ti-Biotechno
j' '
log
.
y (genetic engineering):som edrtlgsareprepared using
recom binantDN A technology''ajH um an jzb'
///jz/,G rowth horm one,
recombintmttissuePlasminogen Activator(1.-tPA '=Alteplase).
Themail'tdisadvantageofthesedrugsistheirhighcost(expensive).
11-Chem istty:
* Somedrtlgs-asAspirin (AcetylSalicylicAcid)and Barbiturates-al'e
w eak acids,whereas otllers-as Ephedrine and Amphetam ine-are weak
bases.
* M ostdtmgsare organic com poundsblltfew drugsare inorganic
elem ents asLithium and Iron.
* Som e dftlgscontain a specific chem iealring)e.g.Steroid horm onesas
Cortisone contain a steroid ring,and catecholam illesasAdrenaline
contain a catecholring.
'
JJ/-Pharmacokinetics..
The term ''pharm acokinetics''describesthe m ovenlelltofdrugs inside the
body,and istlsually referred to as''1p#tat#?ebotlv(,
'''
/.
4.
7:,
$.to the (-
#w.
e''.
''-'-----'----''---''-'---'
'''-'-'-'''-'' ----'''- -'
' - - - - --------'- '-''
--- . '
.
Pharm acokindics include:

1-àbsorption.
l-oistribtttion.
L
j-Metabolism = Biotransfortnation.
n-ïxcretion.
(N.B.:pharmacokineticsaresometimesl-etkrred to as''absorption and
fate'' and m etabolism and excretiollal'e called togetlzer ''elim ination''or
''clearance'').*
3
WhiteKnightLove
lV-P//t7rzl/t
lw
tlt/lv/w pojcc
. .
The term pharm acodynam ics is referred to as ''kvhatthe Jrl/g does to the
bodv''and itincltldes:
A-avechanism ofAc
.tipn:themostimportantlnechanism ofaction ison
specif-
ic ''
receptots''7 btltsom e drugs m ay aeton ejlzym es,celllnem brane,
r
DNA,chenlically,physically,etc.(seelater).
B-pharm acologicalA ctionskthe actionsofthe drtlg m ay be:
l-laoealaetions(also known astopicalactions)wheretlledrug actsatthe
site ofapplication,e.g.skin ointm ents and eye drops.
z-system ic actions:the drug reacllestlle systenlic circulation and is
distribtlted to differentsystem s asCN S,CV S,respiratory system petc.
3-lletlexactions(alsocalledremoteactions):e.g.drugsthatelevate
arterialblood pressure asN oradrenaline lead to ''reflex bradycardia''
through vagalstim ulation.
VLIndications = Therapeutic ?/-$'d.$'

.
'
The diseasesforw hich the drug is prescribed to treatorprevent,exg.
A spirin isindicated '
in treatm entofheadache and tkver,and to prevent
throm boem bolism .
V1-Adverseetfects:
Thisterm describes the unwanted drtlg effectsalld issolnetilues referred
to as''sideeffects''or''toxicellkcts''(seeIater).
V1I-Contraindications:
The diseases in w hich the drug shotlld notbe prescribed,e.g.A spirin is
contraindicated in peptic ulcer.
VlI1-llrsfyrIntqractkon-
- y'
l-Drug-bruginteraetions:when2ormoredrugsareprescribedtothe
patient,theseinteractionsmay be benefieial(favorable)orharrpful
(unfavorable).
z-D rug-lzood interactions,e.g.M A O inhibitorsustxlin treatm entbf
depression interactw ith food containing tyram ine ascheese and yoghtlrt
and lead to seriotlsand m ay be fàtalelevatipllo12blood pêessure.
1.Y-/l(
p2//t?,
.
5'ofzqdm inistratip.
q (seelater).
3
WhiteKnightLove
1-'/JllrlApy/ct?k/pyr/k.
î
A spreviously m entioned;the term ''pharm acokinetics''describesthe
m ovem entofdrugs inside the body,and is usually refen-ed to as
''F hatthq bodvdoesto thedrug''.Pharmacok-ineticsinclude'
.
L-jbsom tion.
2-1 j.:/?'j/?2///taz?.
à-xetabolhm = Biotransformation.
4-fxcretion.
.)
l-A bsorption:
p#fi.
ww. p--
iti
-9.
-
1.)-:
.itisthepassage(transfer)ofthedrugfrom thesiteof
adm inistration to the system ic circulation.
* Itisobviousthatabsorption from any site(GI'r lung,skeletalmuscles,

skin,andinucousmembranes)occursbypassageofthedrugacrossthe
cellm em branew hich ism ade ofplzospholipid bi-layerand contains
minutewater-filled channels(pores).
1
wpassagq ofdrugsacrosscell?z?c/a:?
.
.
w/?e,
$'.
'also ltnown as
''transm em brane m ovem entofdrugs''and itoceurs l)y one ofthe
follow ing m ethods'
.
l-Siluplediflksion (themostil- nportalltlnethod fklrdrugabsorption).
2-Filtration (also fmportalztfordrtlg excretion by tllekidney-see later).
*sim ple difftlsion and filtration are als()know n as''passive tratlsfer''.
3-A ctive transport.
4-Pacilitated diffusion.
.' x .
/*Activetransportand '
,
facilitated dittksion are known as''carrier-lnediated
/transport''
,
*
5-Pinocytosis'.itisan activeprocess(energy-dependent)in wllich the

drug is''engulfed''inside the cell,e.g.absorption ()fvital- nin B i2/intrinsic
tàctorcom plex.
*A ctivetransport,facilitated ditl-tlsiollpalld pinocytosis are know n as
''specialize'd transport''. WhiteKnightLove
*
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m =
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m
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z p .s;s., =
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1
l o ex> = . l=.ev cs - o o ... x. /x .w =r.po o> zm .x.. -
.
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o uz yaox
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y= a o- ='..
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x= - o - q ,a & -
l = = = * vzI lIl % c) = xw x
o ..+ G
.. *. m - > - 2..n-
o ' = c-,=-' R zu
l
t =
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( ml .=
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o ; =o = = > =.. = o = . r.r
- mv.o
z > .. -.xa.
i o e -
r i= o ; o o 1 r o o w x - .- cac .
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WhiteKnightLove
=X
> 1
!
I
r E
m
>
o o
- r>
o jR % -
=
rk o
i c
Drug llm ization:

How mtlchofthedrugisionized(lipidillsoltlble-llydropllilic-polar)and
how much'isunionized(nonionized-lipidsoluble-lipophilic)is
determ ined according to the follow ing rules:
1-M ostdrujsareeitherwealtacidsasaspirin (salieylates)and
phenobarbitone(barbiturates),orweakbasesasephedrineand
amphetamlne.
,
2-Drtlgsarepresenteitherin an acidic'
m ediufn (asthestomacl)which is
higlllyacidic,orurinewhich isslightly acidie),orinanalkalinemedium
(astheintestine).
3-The presence ofan acidic drtlg-as aspirin-in an acidic m ediuln-asthe
StOm aCh-m akesm ostofthe drug unionized and lipid soltlble, so itw illbe
easily absorbed by sim ple difhlsion.
4-The piesence ofan acidic drug-as aspirin-in an alkalinem edium as
the sm alliptestine -m akesm ostofthe drug ionized and lipid insoluble,
andaccordingly itwillbepoorlyabsorbed(* iontrapping).
5-'
l-lte prejenee ofa'basic drtlg in an acidic m ediufn rendersm ostofthe
drug ionized and poorly absorbed;whereasthe presence ofa basic drug in
an alkaline m edium allow sm ostofthe drug to be in the ttnionized form
and alm ostcom plete absorption occurs .
6-lonization Constant= pKaa'itisthe p14 ofthe m edium in w hich 50t% 01: -

the drtlg is ionized and 50% is unionized.
ltis clearthatpKais ''constant''forevery drug,e.g pKaofaspirin = 3,5.
.
Thism eansthatatpl-l3.5,50% ofaspirin isionized alld 50% is

unionized.
7-H endelrson-llasselbalch Equations 'this eqtlation clarifiesthe relation
between pKa,pl-l,and degree ofdrtlg iollization.ltstates that:
pKa= pl-l+ log.Unionized fbrm

tj-
.
ol-acidicdrugs)
lonized fbrm
pK a= pl'l+ log.lonized tbrm

. . .
(j7j.
;j.t;jjjjj(;(jj.(jgjjj
Unionized forl'n
8-The sam e rulesare applied to renalexcl-etion 01'drtlgs:allkalinization of

urineby Nal4C()?enhances(increases)renalexcretion ofacidicdrugsas
aspirin because aspirin w illbe m ostly ionized so itw illbe hydrophilic
and excreted notreabsorbed,butifurine ism ade m ore acidic by vitam in
WhiteKnightLove
C (ascorbicacid)orNH4CI,mostofaspirinwillbeunionizedandlipid
solublejo itwillbe''reabsorbed''by rellalttlbularcells.
O n the otherhand,basic drugs asam phetam ine and ephedrinew illbe
m ore excreted by acidification tsfurine.
Factorsqyecting (modifvinz)Jr/?.eabaorptiom
Thetttctofsthatintluencedrtig absorption can beclassified into factors
related to t
i
he drug and factorsrelated to tlle patiellt.
A -Factorsrelated to the drtlg:

-
1-Lipid splubility and lipid-w atetpartition coefficiellt:them ore the lipid

solubility,the betterthe absorption.
2-Degree ofionization:the m ore the unionized tbrm ofthe drtlg,the
m ore the lipid solubilit'
y and hence the bet-terthe absorption.
3 Valency:fenoussalts(Fe2+)arebetterabsorbedthanferricsalts(Fe3+)
4-Chem icalnature:inorganic drugsare betterabsorbed than organic
drugs. !
5-Pharm atetlticalform tllation:
*A queoussolutionsarebetterabsorbed than suspènsions.
wDrugsthatarerapidly disintegrated (dissolved)in tlïe stomaeh-as
paracetam ol-are betterabsorbed than slow ly disilltegrated drugs as
digoxin.
B-Factors related to the patient'
.
1-Route ofadm inistration'
.
*lntravenousinjection(l.V.):100% ofthedrugl'eacllesthesystemic
circulatiön alm ostim m ediately.
*lntzumujctllarinjection(l.M .):mostofthedrtlg israpidlyabsorbeddue
to the high vascularity ofskeletalm uscles.
*subcutaneousinjection(S.C..I:absorptionislessthanafterI.M .
injectionbecausetheS.C.tisstleisluuch lessvasctllarthantheskeletal
m uscles.
*lnhalation:lipid soluble drugsas inhalation generalanaesthesia are
rapidly and alm ostcom pletely absorbed because tlle alveolihave avery
w ide sufface area and very rich blood supply.
lsublingtial:drugsgiven assublingualpellets-asnitroglycerin in
treatpentofacuteapginalattacks-are betterand nlorörapidlyabsorbed
than orally adm inistered drugs because they reach the system ic
circtllation directly and avoid passage throtlgh (J11'alld the Iiver.
wo ralabsorption isusually variable dtle to the ef-fbctofGlT pnd the liver
onthedrtlg beforereaching thesystemiccirculation' ,thisisknown as
''1StPasseffect''(seelater).
(I.V.> lnhalation > I.M .> S.C.> lntactskin).
WhiteKnightLove
J;
z-surface area ofthe absorbing surface:the m ore the surface area
exposed to'the drug,thebetterthe absorption;e.g.sm allintestine
(* about1000timesthesurfaceareaoftllestomachduetothepresence
ofmicrovitli)andlungalveoli.
3-vasculafity(bloodsupply)oftheabsorbingstlrface:thericherthe
blood supply ofthe absorbing surface,the betterthe absorption'
,eag.the
Sn3a11intestine and the lung alveoli. '
4-stateofhealth oftheabsorbing surface:oralabsorption isgreatly
decreased in theprcsenceefdiseasesofGlT asmalabsorption and
gastritis('Uhich decreasesalcoholabsorption).
I x
s-state ofgeneralcirctllation:in cases ofshock,
'sym pathetic stim ulation
causesvasöconstriction ofsubctltaneotlsblood vesselsand markedly
reducesblpodflow toS.C.tisstles.Drugsasmorphineshouldbegiven
. . '
I.V .in case ofshock.

6-speeific factors:oralvitam in B l2isabsorbed only in thepresence of
intrinsic faktorsyntlzesized by the gastric parietalcells.
FactorsJ//
-cc//pxr(modilving)tprtv/drug J/?.Ntpz'
/p/jtn/?.
(
A -Factorsrelated to the dl-ug:see before.
B-Factorsrelated to thepatient' .
1-Surfacç area ofthe absorbing surface:see before.
2-Vasctllarity (blood supply)ofthe absorbing surfaee:seebefbre.
3-State ofhealth ofthe absorbing surface:see betbre.
4-Specill'ç factors:see before.
5-Gutm ofility:drugsthatstim ulategutlnotility and accelerate gast' ric
eluptyingzknown as ''prokinetic drugs''as l'
netoclopram ide-w illincrease
oralabsofption ofrapidly disintegrated drtlgsas paracetam olbutthey w ill
decrease absorption ofslow ly disintegrated drugsasdigoxin.
D rugsthatinhibitgutm otility and slow gastric elnptying-asatropine-
have opposite effects.
6-G utpl-I:acidic dnlgsas aspirin are betterabsorbed in aeidicm edium as
the stom gph,whereasbasic drugs as ephedrine antlalnphetam ine are
betterabsorbed inalkalinemedium astheintestine(.
)$,
'
/?p?).
7-Gutcontents(food:!-a
9-ndot
herdrugsl: .. . qs'l- :1t.i-
lllood containing C a ,and antaeidscontaillillg A l and M g deerease
absorption oftetracyclinesdue to chelalion.
* e
'r tracyclinesdecrease absorptitln ofCa21'ajld ij-()j)
.
*lk-ood decreasesabsorption ofanlpicillill.

*cholestyram ine and charcoaldecrease absorptioïlofm ostdrugsby
adsorption.
*'l-annic acid in tea and coffee (lecreast)s absotptitln ofir()n.
WhiteKnightLove
!
i
!
* * G rape'
lfruitinhibits P.glycoprotein-which isresponsible forreversed
transportpfdrugsfrom gutm ucosa into gutlum en-and so itincreases
.
'
drug absot.
ption.
8-Firstpajseffect(firstpassmetabolisml'
.orally-administereddrugsmay
bepartiall/orcompletelymetabolizedwhilepassinginGlT(gutfirst
pass)ortlieliver(hepaticfirstpass)beforereaching thesystemic
;
circulatiop.
A-Gutfirk;passeffect'
.
lsom e pep
'icillins are destroyed by gastric aeidity and ate known as
''acid-sensktivepenicillinsl',e.g.benzylpenicillin(penieillinG).
*polypeplidehormonesasinsulin are destroyed by thedigestive
enZym CS.l
*somedrlgsaremetabolizedbythegtl
a-m ethyldopa.
tmtlcosaaschlorpromazineand
B-l-lepaticlfirstpasseffect(muclzmoreiluportantthangutfirstpassl:
*Lipophilj
*som e ofl
cdrtlgsaremetabolizedbytheliver(seelater).
these dnzgs are largely m etabolized by firstpasshepatic effect,
e.g.proprynolol.Otherdrugsareextensivelyfnetabolized,as
nitroglycefin,oralm ostcom pletely m etabolized aslidoeaine.
. û
How toavoidfir- s/passe
.J/e
rc/?.
'
l-lncreasJthe'doseoforally-administereddrugsaspropranololand
nitroglycd in.
z-changel
theroute ofadm inistration'
.the drug m ay begiven I.V .as
benzylpeàicillinanblidocaine,S.C.asinsulin,orsublingual(S.I-.)as
nitroglycer
!în .
i
1
Bioavailà ili ..
#Definitiun:itisthefraction (proportionorpercentage)Oftllecllemically
unchanged drug reaching the system ic circulation fbllow ing
adm inistration by any route.
*Bioavailgbilit'yafterI.V.injection= 1009$.
*Bioavailbbility isvery high followillg administration by inhalation
:
(ïnhalatièngeneralanaesthetics).
+B-ioavailàbilityaf-terI.M .injectionisIligherthanafterS.C.injeetion.
i ility afterS L.adluinistration is highertllan aheroral
*Bioavailab .
adm inistràtion.
*oralbioitvailability isvariable beeatlse offirstpassellkct,and is
calctllated asfollows:
A UCOfi
tl
x !UU
i A U CIV
A UC:A reaU nderplasm aconcentration-timef'
j
- 'K
.
u
nstltve.'
:
1
.
WhiteKnightLove
' :
'j
1
?1, . CoaceMt-ll
'
o.
W J * W *
r
(
oz -.
o
a yo.
-
r
(z) p
o g
r.
=M rr c G %
o
o'
.'.
-r''t ;2'
.$ci
2
. & < > .
>
o R< 1
% v:
f7 (% = % M'
p
m k *rt@
e
-
Q o
- ''D
(p o
j1
-
''
o
=Y
wt c)
'1
-7x>
Q.
m cq
= = o =
p r
M = 0
-.
X = o m
G = > < XM
c o 1 =
- >
G M
G =
e.+ x..> m
:5 :
' o =
=
= ='
o e) q<
& J r =
C) & l
glos- Q ucx.t- fo:
= Cr = . . . -
%*
< = - . .
*
= > r7
- x
= = p
- N
= n
= y)
X..: G
'd = Y
w
:
- G
m c
- ---
= >
> =
Q
>
vn
*) A'
= @Q
O y)
=
w*)
=
7
Q
13 =
C)
,*
'-
o
=7 ;
r =.
>
=
ee
o o
c'
% 7
WhiteKnightLove
l
i
s.
2-D isrtibution:
Oncethetlrug isabsorbed from any site,i.e.itreachesthesystemic
' i
circulation, tisdistiibuted to thebody fluidsandtissuesastbllows:
'
'
'
j
,
A - Compqr
! tm entM odel:
l'
T'
hebopi
yfluids= 42L.representing60% ofthetotalbodyweight
(TBW )of,anaverage70Kg.person and include:plasma(4L.),
interstitia/tluid(10L.),andintracellulartluid(28L.).Theplasmais
refbrredttIlas''intravascularcompartment''anditrepresents6% ot--rBw ,
whereas$eplasmaandtheinterstitialtluidtogether(14la.)arereferred
toas''ekttacellularcompartment''and itrepresents20% ofTBW .
i
! 28 lwiters
q
.
i
i
! 10 Liters
i4 Liters
l
i
!
'
.
l
j
PLASM A ?N7'W,/?,$>F/?a
1AL /AC RA(. Ayvg-gyjuy y
/?/-t7/f) >7-zt7/D
i
(
I x 7 .
ll3rugsare distributed according to one otthe lollow ing
pa//é'/w-t7
. f?fdistribution..
)
/-Olw Cèl??/?/r///7en/M odel:
Drugsthqtare extensively bound to plasm a proteinsand drugsthathave a
,m olecularweightashigh molectllarweightheparin(l'lM W l4)
very high7
anddextràn(plasmaexpander)can notpassthrotlghthecapillary
j '
endothelium and are distribtlted illplasm a only = intravasctllar
compartn!
!ent= 4 L.
2-FJI?/ Cbmpartm entM odel.

D rugs thatare hydrophilic and w ith Iow m olecularweightcqn pass
throtlgh the capillary endothelium butcan notpass the cellm em branes
being lipid insoltlble and ionized-as quaternary am m onium cùm pounds
and N acl-and accordingly are distribtllèed in 2 conlpartlnents:plasm a and
interstitiq!
1tluid =extracellularcofnpal-tm ent= 14 L.
.
I1
WhiteKnightLove
3-khtlticlmpartmentModel:
Drugsthâtareof1ow molecularweight,non-ionized,and lipophilicare
distributçl
d in al1com partlnents both ext-
- racelltllarand intracellular-and
I
accordingly are distributed in 42 L.
I
4 l
SpecialD istribution.
-
.
Som e drpgs are concentrated in eertain tissues,e.g.tetracyclinesare
concentrbted in boneand teeth (Caz+-colltaillingl-iotlilleisconcentrated in
thyroid tij
i.
spe- thiopentone in fatty tissues-heavy m etals aslead and
arsenic iylhairand skin-digitalisin cardiac m tlscles .
i
B-Binding ofDruzstoPlasmaPlote
*ytfterreaching the system ic eirculation, any drug w illbe found in 2
forms;thJfree(unbound)form andtheboundfbrm .
l
1
l
'breeForm /101//7# Form
.
-
Diffusiblt
e. -Non-diffuslble(confinedtoplasma)
-A ctive. p
j - jnactive. .
-
l-iabletöllivermetabolism. -tk'otliabletolivermetabolism.
-
laiabletoi
,renalexcretion(mostly -hlotliabletorenalexcretion.
- by glpmetularfiltration). - - .- - - -Açtsasa''reservppi-''L.--
. - -
.
i
*DrugsVe
)
bound mainlyto albtlminand to a lesserextentto globtllin .
and a-acid glycoprotein.
' I
j ,
*somedrpgsasaspirin and sulphonamideshaveahighly affipity (are
highlyboùnd)toplasmaproteinsandthey displaceotherdrugswith
loweraffit
s
.
lityasdigoxin,sulpho
1 '
x,
nyltlreas(oralhypoglycemics),and
wartarin(pralanticoagulant)ifadlninisteredtogether,whichresultsin
'ncrease in the free ''active''forn'
i loftlle latterdrtlgsand this m ay lead to
severeadverse(toxic)effects:
#A spirin ànd
i
sulphonam idesdisplace digoxin leading to digitalistoxicity.
.
# A spirin >nd sulphonam idesdisplace sulphonyltlreas leading to

hypoglycem ia.
# A spirin i
and stllphonam idesdisplaee w arl-
atin leading to bleeding.
:
lsulphoùam ides displace bilirubin frotn plasnaa proteins,which increases

the tkee bilirtlbin causing hyperbilirubinelnia and may be kefnicterusin
infants.
*1ncondisionscatlsing ''hypoalbulninenlia''asinoldage,liverdiseases,
lnalnutritibn orstarvation;the tkee fotn-
lofdrugs asphenytoin
12
WhiteKnightLove
'
!
i
-
(antiepile:jt
1
.ic)ishigherthan innormalindividualsandtoxiceffectsmay
.
OCCX W itl)!therapeutic doses

.
l
l'
I' lthebound form ot-thedrtlg,thelongeritsduration.Thisis
hem orr
shownwitl
h
I
somesulphonamides.
'
C PIJSSYIWjJJFOSS Svrriers:
-
'
.
!
1-#z7.çt7gt?l
ç. Iacl'
.osqbloodbrainbarrier(#.#.#.).'
-
llwipid solùbleunionized drugscan penetrateB.B.B.and exertC.N .S.

actions,wjereashydrophilicionizeddrugscannotpassacrossB.B.
and have àlm ostno C .N .S.actionsin normalconditions.
B.
k
*P.enicillirscannotpenetratenormalmeningesbutcanpassacross
intlamedme l ningestoC.S.F.incaseofmeningitis(duetoincreased
permeabilsi ty),andsoareusefulintteatment.
'
j
z-passage,acrossplacentalbarrierto /)/z/x.
*M ostdrul
gscan passacrossthe placentalbarrierfiom the m atem al
circulation!to the fetus.
*lwipid soltlble unionized drugspass m tlch m ore easily than hydrophilic
ionizecldrugs
! .
*som e drtp
i
gs-asaspirin,cortisone,AC E inhibitors,benzodiazepines,
x
phenytoin,etc...cause fetalm altorm ations know n as ''teratogenicity''or
''fetotoxicit
;y1,ifgiven in early pregnancy (.1sttrim ester)
.
N B Thalidom
. I ide-w hich w as tlsed as axiolytic and llypnotic-caused
i . .v .
,% ,
amelia oryhocolnelia on a largentlnlberotnewborn infantswhieh was ,
know n as 'y
i-rhalidom idedisaster''
Re cently;jrugsareclassifiedintocategories' .A,l3,(*
according tô theirpossibleteratogenic etlkct.
-
3
.
,D,andX
,
l-passageithrough breastm ilk:

.
lklostdrur 'scan passthrotlgh breastm ilkto thestlcklingbabies' ,someof
which ma# causeseriousadverseeffbctsasmorplline,fluroquinolones,
radioactivt iodine,etc..
*llasicdrtigsare ionized and ''trapped''in breastm ilk'becauseitspl-lis
moreacidic(= 7)comparedto plasmapH (= 7.4.
).
*lwipophilic drugs are retained in breastm ilk because of itsrich fàt
. :
content.
D-Redistrlbution: '
Highly lipophi
'! lic drugsas benzodiazepinesalld barbituratesespecially
thiopentone(used asI.V.anaesthetic)areconcentrated in C.N .S.becatlse
WhiteKnightLove
ofitshigh lipid conentand rich vasctllarity,thentlley areredistributed

'
from C.Nlj.toadipösetissues,skeletalmuscles,andothertisstles.
Re
d distribtjtionterminatestheactionofthedrugandaccordinglythe
uration pfthesedrugsdepends on redistribution and noton m etabolism
or excretipin.Thiopentone isdescribed as ''ultrashortacting bàrbiturate''.
I
.'
j.
C-Ap
-parqI
ntvta/l/zz,cofdistribution (P'
,/-u
*-1-heappAlrentvolume ofdistribution (Vu)isarough measureofdrug
distributiln;thelargcrthcVd,themorethedrugdistribution
!I
.
*'
T'
heappaIrentvoltlme ofdistribution isealculated in liters(orin liters
/Kg.)accqrding tothefollowing equation:.
1 Amountofdrug
!
r),-toncentration tnplasma
I
t
la (inmg) .
CIU Wt'W'
C
l (inmg.//??f.
)
A:Am ouptordoseoftheadlninistered drtlg.
C.
'Concel
'jtrationofthedruginplasma.
r
-
* SignT/cl inceofrim.
l-Tlàeterlil ''apparent''indieatesthatitmaynotbeatruevalueasinthe
*
caseofdiyoxin which hasa Vuolr500 literswlziellismuch higherthattlle
.
totalflqid1
i
volume(42L.inanaverage70 Kg.persoll).
z-llligh Vkindicatesthatthe drug is distributed as a nm lticonapartm ent
i
modelotLa
(
shightissueconcentration.
3-Low Vuj
.ndicatesthatthedrugisretained inplaslna(intravascular,one
compartmkntmodel)mostlyduett)higllbindingtoplasmaproteins.
4-lonow ing'the V dallow sthe estim atiollofthe ''loading dose''w hich is
; . .
the initialdose required to reach a specific drtlg concentration,and also
,
allow sm eàsurem entofthe totalam ountofthe drug in the body:

A7
L k/x c
s-D rtlgs 1 1th low Vdasaspirin are highly botlnd to plasrna proteins
i
m eaning thatthey a have high plasm a concentration,thatisw hy
hemodialysisisusefulintreatmentofacutetoxicitybythesedrtlgs.
Itis clearthathem odialysisisnotbenetieialin treatm entofacute toxicity
by drugsw'ith high V dbecausethey have low plasm a concentration beiltg
highly disfributed orhighly concentrated in tisstles.
14
WhiteKnightLove
'
*
I
i
1
.
I
Factorsa 'ectin distribution..
l-physicop,çhem icalproperties of the drtlg:
- lsipidsoltlbility.
- D egree qfionization.
l
- M oleculgrw eight.
z-plasmaplroteinbinding(seebefore).
3-passagel
jacrossbarriers(seebefore).
1
I .
l'
I
'l
j
.
I
I
!
I
l
)
!
!
I
1
-
i
1
l
.
1
J
I
i
i
l
!
.
f
.1 !
i
!
WhiteKnightLove
'
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. q.
1
3-M E TA B OLISM =B IO T M W ORM A TION
!
* Thtse are chem icalreactionsthatoccurm ainly in the liver .
* ,rhçlaim ofbiotransform ation reactionsisto ,,convertjjpopjjjjjc

li!
(p idsoluble)drugsintowater-soltlble(hydrophilic,ionized,or
P('
)l;
h.
rlmetabolitesto beeasilyexcretedinurine.
!clearthatw ater-
*Itiy1excreted ''unchanged'
arer
solubledrugsdonotundergometabolism and
'in urine.
* Ontthe otherhand,lipophilic drugs-aftert'
'
iltration through the renal
glo eruli-w illundergo ''reabsorption''by the renaltubularcells,
m a ing renalexcretiofiofthese drugs very slow .So,they are
i
abolizedtobeconvertedintowatersolubleform topromote
m e'
â
thelrrenalexcretion.
I
PhaseslofBiotransformationReactions:
1-Phaje 1Reactions:
*Thes1
èare''Non-synthetic''reactions.
* The drug undergoeseither:oxidation, reduction,orhydrolysis.
*Phast1reactionswillresultin oneofthefollow ing:
1
. I
1-Conyersion ofan activedrtlg into an ''inactivejfmetabolit
.e.,l,hisis
the m oi
s
;tcom m on result, e.g..
.
Hydrolysis
Acetylçholine * eholine + acetic acid
2-Cohs
yersion ofan active drtlg into an ''active''m etabolite, e.g.:
ù Oxidation
!
pjayyjajetjnjactive).----.. ,.F paracetamol= acetaminophen
(3UtiVC).
' ! ytayjjtljgjj)
Chloralhydrate(active)----..
- ---'
.
--.----*'trichloroetllanol(aetive).
é
3-Conkersion ofan ''inactive''drug into an ''aetive''metabolitealld in
this case the parentdnlg is know n asa -
'
'
-
.ptç
)p.(#lg'
--
'.
>e.g.cortisone
-
I . .
(inadi ye)ischangedintoColtisl3l=hydl-octlltkSojjo(aotjvo,and
enalap'r(iltinactive)ismetabolized into ertalaprilate(active).
; Oxidation
jjujpj-afnjne #.dcsiplXlllille.
4-V ely rarely;a t

.
oxic m etabolite is fbrm ed,e.g.m ethylalcohol
(methano
'
l)ismetabolizedbyoxidatiollintofbl'maldellydewhich
catlsesl
Jp
* elm anentbl
'
indness,being rd inotoxic. ' ..
!!Axt >- $) -jJ 9Z11 t.
?t
.. %f.. i$#J
yotQxt4s.w,4?t-.aJ:dazs..11ax1-..
,
. .
16
WhiteKnightLove
1
i
i
,
ll-phase11Reactionsr -
''ThesearJ''synthetic''reactions.
*-f'
hedrugI
;ora m etaf)olite resulting t7rom phaseIreaction is''conjugated''
w ithxan enj
i
dogenous polarcom potlnd asglucuronic acid,sulphate,
glycine,aretate,glutathioneormethylgrotlp.
Aphasellrfeactionsm ostly resultin drug inactivation,with some
exceptionj1asmorphine(active)which ispartiallyconverted intp
morphineq-glucuronide(activemetabolite),andtninoxidil(inaetive)is
conjugatebintominoxidilsulphate(aetive).
N.B.mostldrtlgsaremetabolizedbyphaselreactionsfollowedbyphase
11reaction/,undergophaselreactiononly,orphase11reactionsonly.
l7ew drugk1asisoniazidismetabolizedbyeonjugation(phasel1)followed
by oxidatijn (phasel),i.e.thereisf,reversalotworderoj-tjyopjjases1..
h .
!
I
TypesofEnzvm
i '''.
esResponsible fbrBiotransfopnation Reactions:
M içrosom alEnzym es N on-M icrosom alEnzym es

l
l- Found ili
lsm ooth endoplasm D lc l-FoundXln the cytoplas
= m and
retictllum 1
ofliver cells, thatis why m itochondria oflivercells,skin,
tlzey arerll
ferred toas ''hepatic'' Gl'
1',lungs,and in plaslna.
microsomjlenzymes(l4ME).
l
z-They catalyzethefollowing z--rlley catalyzethefollowing
biotransfojim ationreactions: biotransfornlatiollreactions:
-
oxidatioltI(by cytochromeP -oxidatioll.
450=CYPkIs()enzymes). -lteduction.
-Redtlction. -l-lydrtllysis.
I.
lydrolysp
ks . t-a
-
-olljugatitlllexce
-ptNvith
-
conjugatl:onwithglueuronieaicd j
g tlctlronju akyj
d .
On/y .
l
j
)
I
!' r.
j
3--l-heiradivityvariesw ith age,sex 3-* lheiractivity variesw ith age .
ofthepatiknts,starvation,liver andsex,butisnotaffeetedby
diseases,:nd by drtlgs:their starvation,liverdiseasesnordtugj.
activity isincreased ordecreased
by drugsknow n asH M E inducers
and H M E tinhibitors;respectively
(seelater);
g '
4-Acton lkpophilicdrtlgsu* - - - - - .-- -
1 A ç/-:+l
-
-.-.- ...-
.l1ilic drtlgs. # --.
l f1r:l) - - -
17
WhiteKnightLove
l
!
l
'j
!
l
FactorsAffecting HeplticM icrosomalEnzymx actj-
yjty: -
l-lhefxej
c/of
'Drugs:
*Some drngsincreasetheactivity olxhepaticm icrosomalenzymes
(HM E)and!
Iareknow n asHM 'E indtlcers()ractivators, whereasother
drugsredrceorinhibittheactivityOt-l1M E andarethuscalledHM E
inhibitors;!
* Exam ples ofH M E inducers:phenytoin,phenobarbitone, rifam picin,
n icotine(tkbaccosmoking),testosterone(androgens),carbamazepine
x 1 x
,
griseotulv n,chronic alcoholingestion, * coftke and tea.
* Exam pl s ofH M E inhibitors'
.cim etidine,chloram phenicol
t ,
contracept/ve pills(containing estrogen and/orprogesterone),
ketoconaztj
om eprazolj
le,erythromycinnfltlroquinolones,allopurinol,grapefruit,
è, * stllphonam ides,sodium valproate,M A O lnhibitors,
isoniazid,jndacutealcoholism.
*lm ortartceofHM E induction:
*HMEinqucersincreasetheirownmetabolisln,whichmayleadto
tolerance lit
nd dependence,e.g.pllenobarbitone,nicotine and chronic
alcoholism .
*I'IM E inpucersincreasethe.metabolislnofotllerdrugsgivenatthesame
j.
. .
tim e leadipg to deereased aetivity ofthe otlkerdrugs ,l-hislequjrus
, . .
.
increasingi
lhedoset)ftheotherdrugs.
.Som e H M1E inducers asphenytoin inerease thenzetabolism ofvitam ins
asfolic acijl,vitam in K , and vitam in I3,leading to m egalobl/stic anem ia,
.
'
hemorrhagh,andosteomalacia;respectively.
*HM E indI l
tlcersasphenobarbitoneareused intreatmentofmild
hyperbilirqbinemiainneonatesastheyinduceconjugatjoyjot-bilirubin.
*
--lmp
' -
oljant!t-ofHM E inhipjtorî)
-
A dm inistrg'
tion ofHM E inhibitorsw ith som e drugs- asw arfarin,
digitalis,oralhypoglycem ics,tlleopllylline-m ay lead to increased plasm a
levels ofsuch drugseven w ith therapeutic.doses,which m ay lead to
''toxicity''i
!hatiswhyweshouldreducethedoseofwarfarin,digitalis,
oralhypogt
ycemics,andtheophyllineifgivenwithIIM E inhibitors.
I
I
2-Age: I
:
Theaetivity ofHM E islowerin extrem itiesofage;i.e.neonates
(especiallypifpremature)ando1dage,sotheysltcluldbetreated with
low erdosetthan adults.
3-u%x Getlder . '

M ale sex hbr
l
m ones ( androcens
''' ''''''
)
'''
actas LIM E indtlcetsw hereas lkm ale sex
..
hormones(estrogenandprogesterone)aetasI-IME inhibitors.-I'
l1isisan
18
WhiteKnightLove
'
1
ë.
importantta
! usewhyfbmalesreceivelowerdosesthanmales(of-thesame
.
ageandwyight).
4-patholo icalconditions.
.
LiverdijejsesascirrhosismarkedlyreducetheactivityofHMEandthe
doseofàrtlgsmetabolizedbytheseenzymesshouldbeadjusted
accordingl
I
toliverfunctiontestsx* e.g.theeffectofdiazepam onCNSis
increased,lwhich m ay lead tocoma ifgiven in therapetlticdosesto
patientsw 1
ith hepatic im pairm ent.
.
5-starvaii
'
I
on:
'
ln cases o starvation,there is m arked depletion of.glycine contentwhich

inhibitsglcifleconjugation.
6-Geneti 'actors Pharmaco eneticsh'
.
Thereis arked variation (polymorphism)in thuenzymeactivity among
thepopulltionwhichintluencesdrugactionandtoxicity.
In additio ,genetic abnorm alitiesm ay resultin defective orabnorm al
enzym es; .g.genetic defed in pseudocholinesterase enzym e greatly
reducesm -tabolism -and increasesthe action-ofsuccinylcholine
(skeletalpmsclerelaxant)andmayleadto''apnea''.'fhisabnormaldrug
response)uetogeneticdefectisknownas''idiosyneracy''.
l
(
'
j
J
I,
I
l
i
i
!
I
19
WhiteKnightLove
'
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4-EXc etion:
D rugsan theirm etabolitesare excreted by the follow ing routes:
l-K idne Renalexcretion ..

.'rhe m os im portantroute ofdrtlg excretion is excretion in urine.
k
.'
l'
he drtl tm dergoes one-orm ore-ofthe follow ing processes In the
nephrons:
l-Glomer 1arFiltration (passiveprocess):thefree('unbound)form ofthe
drug is filered,depending on the glom erularfiltration rate.
z--l-ubulatReabsorption (passiveprocessl:theunionized (lipophilic)form
ofthe dru undergoes tubularreabsorption.
3-rfkbula Secretion(activeprocessl:somedrugs-aswellasendogenous
substance asuric acid-are actively transported illto the lum en ofthe
Proximal onvolutedtubules(PCT)ofnephrons,e.g.penicillins',
cephaloso,ins,probenicid,thiazide and loop diuretics,etc...
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herearli2activetransportsystems(carriersl;onefbrsecretionot-
organicajidicdrugsaspenicillinandprobenicid,andtheotllerfbr
secretionj
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forganicbasicdrugsasephedrineandamphetamine.
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penicilliy andprobenicidcompeteforthesamecarrieraresecretedby
thesamei
transportsystem (carrierlkthatiswhyprobenicidincreasesthe
duration oj action ofpenicillin,as probenicid w illdecrease tubular
secl'etion ùfpenicillin leading to increase in itsplasmaconcentration.
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.R-lle H ftlrine chan esthe rate t)f tlrillalv excletjtjjjoj.jjrtjgs-
. . .
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alkaliniza ion ofurine by NallCO3increases tlrinary excretion otacidic
drugs asa pirin and phenobarbitone,because m ostol-tlle drug w illbe in
the ionize
' hydrophilic form , w hich iseasily excretttd and notreabsorbed
(iontrajpi
!ng).
Ontheotherhand,acidification ofurineby amm onitlm chloride(N H4Cl)
'
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amphetantineand ephedrine.
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These fac s are clinically usefulin tregpnentofaçute drtlg toxicity by
- .
increasin theirexcretion in urine through changing the pl-lOfurine.

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Som cdrugsmay beexcrded by:
A Bile.som e drugs are excreted in bile in one oftwo form s;free drug
-
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(active),à,sampicillinandrifampicin,t)rconjugateddrug(inactive),as
luorphlineiand phenolphthalein (achelnicalIaxative). .
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Som e druIsexcreted by bile m ay undergo yjentero-hepatic recyclejjwhich

prolongs le duration ofaction ofsuch drugs.
B-saliva'
. .g.morphine,iodine(whichmaycauseametallictasteand
inflamma'ionofthesalivaryglands),andrifampicin.
C-stomac :m orphine is partially excreted in the stom ach;thatiswhy
stom ach ash isperform ed in case ofacute m orphine poisoning despite
the factth tm om hine is adm inistered intravenously.
D -lLar e ntestine Stools : drtlgs thatare poorly absorbed orally as

aminogly osides(e.g.streptomycin)andsometetracyclinesareexcreted
in stools.
3-Respir tol ,$'stem .inhaled generalanaesthetics,w hethergasesas

nitrousox'de,orvolatile liquidsaslzalothane,are excreted by lungs.
l-sweat. ery few drugsare excreted in sw eatqsrifam picin and 1312.

v
s-Breast ilk'
. m any drugscan be excreted in breastm ilk and can affect
sucklingifants,e.g.laxqtives(asphenolphthalçin),antihistamilzics(in
common old medications),oralanticoagulants(aswarfarin),antibiotics
(aschlor: phenicol,tetracyclinesandtluroquinolones),morphine,
antithyroiIdrugs,etc.
.ltisw ell now n thatbasic drugsas am phetam ine and m orphine are
''trapped'' nd excreted in breastm ilk (seebefore).
N.B..rifa zpicin is excreted in tlrine,sweat,saliva,and evellin tears
causing o nge-red discoloration ofallthe fluids.
è Sweat landsand mammary glandsare'called ''skin glands''.
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1 Freely you have received; freely give.
*G ive Re jon Ex lain .

l-A spirin is partially absorbed from the stom ach.
2-N aH CO3isessentialin treatnw ntofacute salicylate toxicity.
3-Acidifa tion ofurinebyNH4CIorascorbic acid ishelpfulintreatment
ofacute a phetam ine toxicity.
4-salicyl- esare betterabsorbed from the upperpartofthe sm allintestine
than from itsterm inalpart.
5-In case fshock;m orphine should be given I.V .and notS.C.
6-Drugsa e absorbed m ainly from the sm allintestine notfrom the
stom ach.
7-The dos oforally-adm inistered nitroglycerin is m tlch higherthan the
S.L.dose.
8-ltisnotadvisable to prescribe aspirin to patients treated w ith w arfarin.
9-sulpho am ides are contraindicated in late pregnancy and neonates.
lo-llem o ialysisisbeneficialin acute salicylatetoxicity.
1l-rrhe d se ofdrugsm etabolized by l1M Es ishigherin sm okersthan in
non-sm ok rs.
ll--l-he d seofw arfarin should be reduced in patientstreated w ith
alloptlrin 1.
l2-The d se ot-theophylline shotlld be increased i11patientstreated w ith
phenobar itone.
l3-l-lypo iycemiccomamayocctlriforalhypoglycemicdrugsaregiven
w ith cim e idine.
l4-severe hem orrhage m ay occurin patientstreated w ith w artl-
trin and
consum ip grape fruit.
*Enum er tq:
l-Factors affecting drug absorption.
1
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2- Factors affecting oralabsorption.
3-Factorjaffectingbioavailability.
4-Factors affecting drug distTibution.
s-FactorsI
affecting hepatic m ierosom alenzym e activity.
WD e-f
me.J
- Absorptit
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l
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PK a. 2
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- Bioavailability.
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Routes t?/'p r/zf A dm inistration

There are m ain routesofdrug adm inistration:
1-E ntera route:drugsare given through G IT.ltiseither:
A-Oral( .0.). B-Sublingual(S.L.). C-Rectal(P.R.).
2-Parentralroute:includesinjectionand S.C.implantation.
3-Inhalaion:eitherforlocalaction(astreatmentofbronchialasthmala
orforsystmicaction (asinhalation generalanaesthesia).
4- To ica local.on skin and m ucous m em branes aseye, nose,ear,and
vagina.
R ollt The drug A tlvttntttges UD -

isadvant
-- ages
should be
l-Enteral:
A -oral l-stable. l-Easy. N otsuitable for:
2-N otirritant. z-convenient. l-Emergencies(dueto
3-Absorbable. 3-Economic. delayed onsetofaction).
4-saf'
e. z-unconsciouspatients
s-suitableform ost (forfearofaspiration
drugs. pnetlmonia).
3-lrritantdrtlgs.
l 4-unabsorbabledrugsas
. am jnoglycosides
(streptomycin).
s-ullcooperative patients
(aschildren).
l 6-111presenceofnausea
and vom iting.
7-flrugsw ith alm ost
I com plete firstpass effect
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8 Aj
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orajn e).
ion is affected
by the presence offood
B-sublinglhal l-stable. l-lkapidonsetof andotherdrugs.
(S.L.I:e.g.I z-solublein action.
nitroglyceltin saliva. z-Avoidsfirstpass
pelletsin j 3-palatable. effect.
acute angilj
'al 4-cfpfective in 3-overdose ef-fects '
l .
attacks. sm alldoses. ean be avoided by
swallow ing ol'
spitting ofthe
' ellç/ .
. - . . ----- -- - - ..--- - - - - ..- - - - -- - - - - - -
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C-Rectal: ln the form of Can be used iforal l-inconvenlenttbrm ost

suppository and route is ineffective patients.
enem a.Enem a is as in: z-m ay catlse rectal
either:l-retention Unconscious- intlammation(proctitis).
I enema(M gSO4, Vomiting-lrritant 3-variableabsorption
glucosersteroids) drugs- especiallywhenthe
z-evacuant Uncooperative rectum if ftlllofstools.
enema (e.g.in patients-Drugswith
constipation). extensivefirstpass.
2-1n ectio : A lIdrugs should
be sterile and
pyrogen-free.
A -I.V .: l-m ostdrugs l-Tlle m ostrapid l-A llergic reactionsas
(bolusor should beslow ly routeso usefulin anaphylacticshock.
infusion) injected. emergencies. z-ltapidinjectionof
2-O n1y aqueous z-A chieves 100% am inophylline causes
soltltionsare bioavailability. severe hypotension and
allow ed. 3-u sefulforhighly arrhythm ias=velocity
irritantdttlgs. reaction.
4-useftllin 3-l3yrogenic reaction m ay
tlnconscions occtlr.
patients. 4--l-hrom bophlebitis.
I s-uselklfordrtlgs s-rl-ransm ission ofdiseases
notabsorbed orally. as hepatitis B and C.
6-useftllin 6-Extravasation ofthe
vom iting. drug m ay cause necrosis
'/-l-argevolum es (seenoradrenaline).
can beyivenby '/-Avoid oily preparations
1V infusion. and stlspensionsto avoid
em bolism .
B-I.M .. l-soltltions. Rapid onsetand l-A void highly irritant

zsuspensions. highbioavailability. drugs(toavoid
3-Oily intlammation).
Preparations. z-lleparin should neverbe
4-M oderately given IM to avoid
1 irritant. hem atom a.
l 3-painairritation.
)
C S.C.: l
-
i A s1M .Use Only Slow erand lowel' .j'
W Otsuitable in. -Sjlock.
non-irritant bioavailabily than z-irritantdrugs.
drugs. IM (lessvasculaf). 3-lar evolumes.
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3-lnhala ion G ases-v olatile l-llseftllfor * lrritation ofbronchiby

liquids-A erosol system ic actionsas som e drugs-irregular
(solutiongiven genoralanaesthesia dosage.
by inhaleror and localactions as
nebulizerl-finely t'
reatment()f
m icronized bronchialasthm a .
powder(given z-very rapid onset

byspinhaler). andveryhigh
bioavailability if
system ic action is
desired.
4-To ic l:
A -skin: l-o intm ents, A bsorption ofsom e
cream s,and harm fuldrugsassteroids
powdersareapplied (cortisol)especiallyin
fbrIocalactions. children,
z--l-ransderm al organophosphorous
delively system compotmds(in the form of
(TDS)as insecticides),and picotine
transdermalpatches (in workerscollecting
whichareapplied tobacco leaves)mayoccur
forsystem ic actiolls causing system ic actions.
l asnitroglycerill lt
.
avoids 1Stpassand
has long dtlration.
l-used fbrltx al Undesirable system ic

B-Nlucous actions,e.g.eye ad ionsm ay occur, e.g.
membranps: dropsin glatlcoma. timololeyedropsused in
N ose. 2-M ay be tlsed for glaucom a m ay cause
-
Ear. system ic actionsas severe bronchospasm in
-
fîye. nasalvasopressin asthm atic patients.
-
M outh. (AD1-l)intreatment
ofdiabetes
1 insipipus
.
-- - - -
l
N .l1.:Drggsgiven orally al-e liable to 1stpass lnetabolism ,w hereas(jj-ugs
given S,L.i
j,injection,inhalation, and by 'I-DS avoid lStpasseftbct.
* Skin a 'sor tion can beincreased b .
l-lnunctin(rubbingofoilydrugs).
z-lontopàoresis(galvaniccurrentforwatersoltlbledrtlgs).
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*o ther outes o A dm inistratlon:
-
otherm thodso in'ection:
*lntra-d nhal:sensitivity testsand vaccines.
wlntra-a erial'
.thrombolytics(fibrinolytics),angiographyandincancer
chem oth rapy.
*lntra-c diac:adrenalineincardiacarrest(cardiacresuscitation).
*lntra-aricular'
.cortisolin treatm entofarthritis .
llntra-p ritoneal.in peritonealdialysis .
llntra-th cal:in spinalanaesthesia and in treatm entofm eningitis .
** lntracameral:injection intoaqtleoushumor.
** Intraosseous'
.injectionthroughtheshaftoflongbones.
-
subcttta ct?lz: im lantation:e g.contraceptives asnorgestrelw hich isin
.
thç form fa solid capsule(pellet)implanted undertlleskin,from which

thehorm neisreleased foralongperiod(upto5years).
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*How t ,rolon the duration ofaction ofdrttgs .

.
l-D elay bsorption by:

-
A dd vas constrictorsas adrenaline to localanaesthesia .
-
Addoil othedrug(asvasopressill).
-
u se sus ensionsasprotam ine zinc insulin.
-
S.C.im plantsascontraceptives(norgestrel).
-
use1on '-acting preparationsassustainedrelease (SR)preparations,also
known fiscontrolled release(CR)and timed-release(TR)preparations.
2-Useprlarationsthatarehigllly boulldtoplasnlaproteills(longacting
sulphona ides).
3-Decrea e m etabolism by H M E inhibitors.
4-D elay r nalexeretion e.g.by adding probenicid to penieillin.
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.
;
Jh ( :.,-
* Receptorsarespecificproteinm acrom olecufespresenton thtcell .
m embrane(e.g.(z-and p-adrznergicreceptors,and muscarinic and

nicotinic receptors),insidethecytoplasm (e.g.receptorsforsteroid
hormonesandvitaminD),andinsidethenucleus(e.g.receptorsfor
thyroid hormones).
* A ny chem ioalsubstance thathas the ability to bind to a receptoris
called a ''ligand''
* Ligandsm ay be:drugs,horm ones,orchem icaltransm itters
(neurotransmitters).
Theabilityoftheligandtobindtothereeeptorisealled ''
aFinilv''.
. A ffinity m ay be due to the factthatthe shapes ofthe ligand and the
receptorarecomplementary(KevandLocktheorv),whicllallowsthe
drtlg to ''fit''onto the receptor.
* D rugs Acting on recçptors are classified into:
1-A GtlN fuîtF,.

j'x'
AAgopistsaredrugsthatactivate(stinlulate)tlle receptors.
#'l-hey are characterized by having:
A -A ffinity.
B-Et4ficacy(intrinsicactivi.
ty=* 1A):agonistshavetheabilityto
chanyeYepgt
-i
-yi
.t
.yofthecell;eitherbystimulationorinhibition(e.g.
'
Yiplipçac!j#.
àtfl
-
.
janagonistonp-receptorsintheheartcatlsing
,.
'% . .v.
stlmulation o?cardiacpropertiesashearttate,and aetsonj-receptors
in the sm ooth m tlsclesoftlle intestine causing inhibition or
relaxation).
'
'' o- C-RaA%isdoct
)tkV'...j rate ofassociation and dissociation:
alion 'w,''
*'-,
*''
zvF/z'v
.
ru o -y . rj
..
Ka -''= - ',/
',
'
k
v
.
sk' .-c,zaco,.
e
()+.R. . D R com plex---..,.--'
.1 drug res))tlnse
D issociation
(17 drtlg-1t.
.
.
.
a'.rateot:assoeiation-Ku.rateofdissociation).
receptor--K. .
1
MExam plesofagonists:A cetylclltlline-A drenalille-N oradrellalille.

ATlleresponse(effectoraction)oftheagonistdependson:
l--fhe num berofreceptors occupied by the agonist:the m ore tlle
num bertlle m ore theresponse.'l-llis isknow n as ''occupation theory ''.
.-2..2-22U 72:2
28
WhiteKnightLove
h
,
-.
333
2
L
;
.
6 .
-
-4
':'',
. ''
,'
.....
,4
!'
.::::::
ë5).@t.
,---
.!;,
t'
i.k
r'(
k..f
'
'n*>' '.
y''> l
.
,/ '. à
'
,.
'
z-ouantalDose-ResponseCuryez.
.. ;C
.
?' u'
-fhedoseorlog.doseofadrugisplotled versusthenumberor
'),
V
.. percentage ofindividuals orexperim entalanim alsreceiving the drug.
:7-...,
I
.. M edian Effective Dose = EDs :itisthe dose thatachievesa
-
'
.'
.
partieulartherapeutic effectin 50ty0of individtlalsorexperim ental
mzim als.
- M edian ToxicDose= TDsj:itisthedosethatinducesa specifictoxic
effed in 50% ofexperim entalanim als.
- M edian LethalD ose =LD X:itisthe dose thatcatlsesdeath of50% of
experim entalanim als.
-r
rherapeutic lndex = IvD 5e/ED 5a.Itisa m easure ofdrug safety;the
higherthe index the saferthe drug.
Z-AN TA GONISTS = BLOCKERS:

A ntag6nists are drtlgsthatblock the receptors thus preventing the
adion ofthe agopist,and are characterized by the follow ing:
A- Affinity.
B- . .
efficacv (Nze
=
roa efficacyl:no chan e, in tlleactivity ofthecellin
the absence ofan agonist,buttlley reventthe action ()fthe
@gonist.
C- 5-1(
.....
.
)W)rate ofassociation.lm d dissocm
ition. t
/.gy'
t?r L-.j,.
q'''
.... .----
x .
/ztv -'
-
a(. j
f
z -.
#
.-
-
.
r'c? sczd-o,.'
z
-.
@'G?ik
-
m/ .
'''f.
-y
) .......j
-
3
'
S
-w.- ''.- .- -
.!.->.'
y:(j ?
..-.
.,.
)jTypes
*
.
ofPharm acologicalantagonists'
. (
.. ..
aysj,
0
/ )r
..
?y
)..':
s,v,'
L:-'
ï,
; ,
l-colnpetitiveA ntagonistszthere is com petition betw een the agonist
'
.
>x '
.. ç ).-'<,'
-'--' '--*...p-.
okIcv<
ào
'-m'.
Q /jt/,
tLv.alydt
x$s-,
lguta onlst lonthesamereceptor,andexqjp-t;.a.g
'v----- -z-- -
-u
-ol
-lj-
stcandisplace
e'1'' ' tlle ahtagonlst.Exam ples'
.A tl-opille-làl-öpralloltll-llrazosin-curare.
Com petitive antagonistscatlse ''parallelsllil? ttt)the rightwith sam e
eff'icacy''ofthe log.dose/response ctlrve ofthe agonist.
rr
, .theantagonistittlltly
z-Non-com petitiveAntagonists' --be dis lacedby -
J.'
31-'
l
êt -eovzgas-excessagonist.They cause ''non-parallelshittto the rig--htw ith reduce
sw r .
efficacy''ofthe agonistlog.dose- response ctlrve.

- ' '
' >.
: N on-com petitive antagonistsare ftlrtherstlbdivided into: .
.
3/',1b''i.
:
'
/s
tpt.;:1--),-.-'-'t>:*
. ,
. kr-
--'
. .
i-peversibleAntagonists:theenkctot-theantagonistisot-short ' ê'J.
' .- .
duration becauseitisrapidly nwtabolized,e.g.succinylcholine(non-

compditiveneuro-m uscularblocker).
ii-lrreversibleAntagonists:the etlkctofthe alztagonistis plmlonged
hsç.,' ''
becauseitbindsto thereceptorby a''coycltptsbéJl' ld'',and itseffectis - -
tenuinated by syptlptqj&pf
..!1q receptors,e.g.phenoxybenzapzine
- -
(irreversiblea-blocker). k
?o ,.'
' .
30
WhiteKnightLove
' !
I): sj.,/
,4xe
f f,y< ? '
s* 4w.>
...
' ('.</'.r.>,-.w
x.a1 .. c
, .
J
wo . /
' ,
V 6'? 1S
.
s't o.
+
9,'Jy. cT )s.-
, /
J.
f :î'$?.e
czg. .zry
. t'
''
-'
y. $s4.
;,.,.
e' o.-
,
LJ
t4
Y
*
<
X
&a . t'
L ..s.
'
* Parallelshiû to thelight. s*'-kxo

-abpjparal
., x'.'
à,-.
lelshifttotlaeright.
'
*stzn'
teçfticacy(Emax). 1-p.
.-
,-.:-
1Jefficacy(Euzxisreduced).
,
.
4%1
tt
rr
à!q
.ç
!
? MW .v..4''''
-
.
l> z
('
.
yjgonjstayter Agonisttz
/cr
*-
'.', Competi
tive Antagonist Non-competitive Ahtagonist
G raded D ose-Response tn
..lfz-vewvft n//t)wj?kg dfferentfl?
- /ptw (tf
Wz?/yzxg' t
qlz/j,
s'/x
3-PAR TIA L ,4GONISTS tD ttttlist%l. /.')J..?'.1 1

slmlq.xk.-jj
./?<
>t.'eix y
%. krg9
Few drugs actaspartialagonistshaving the tbl . low ing characters:yj.d').,ty?',o.ypz J .
. ..
.
6 .
A -A ffinity.
J3-M oderateefficacv(lessthan theagonistand higherthan tl4e
antagonist).
C-Slo'lyormoderyterateorassociationanddis>ociation(slowerthan
.
tlleagonist).
1yz
ar
N.
tial
.'k
=àgoni
..
-' stsare used clinically asantagonists.Exam ples:som e
Is-blockersas..xpxprvnotol,pipdo lolrand aeebutolol-N icotine in large
w. .
dose-succinylcholine. /' .t
k'h/m ..-.
:r-;;;J-lnj''
?-t *
ri11 u
o/t.
r'z-'-'.
-..
.
::);;Jt
,
oj
g.
;,
y
WhiteKnightLove
Tvpes ofReceptors and Siznal-lkansduction

M echanism s,
1
Receptorshave 2 m ain f'unctions;to bind ligandsand to initiate a
''response''oreffectin the cells by signaltransduction.
'-tL
y,
.
(
, )st,.
' ,
' There'are 4 types ofreceptors according to the signaltransduction
t, Njxt.,,. mechànism responsible forinducing the response ofagonists:
, .
.
1
'7
'jg
n...
,
'
kq
; . t .
,.
..
..
,
...
: ;i
, -
2(',
..
':
r
q
.
'' (
'
t v
.
u
-
r
j
v
L
b/
.
-
'l
-
'j
vl
ry
l
:
'î ' y >so*J.-/0
-
'n-ChJ/l/ldjjjyked yzcgpjpyx= Lkayd.paktjytlyjchgyyvjs
.
A-
V ,f7
s.'
They are located in the cellm em brane on the gatesofion channels.
z,d9
;r.W'
A ctivation ofthistype otw receptors by specific agonists leadsto
tç.
,
1*
ï''''h''''' '
..
changein theshapeofthereceptor(coflformationalchange)followed
r
'
t
. by opening ofthe gatesofspecit.
,
.c ion channels Exam ples include'
i . .
Nicotinicreççptors(N)'
-
.
Theyareformed of5subunits' .2a,1j3,1y,and lô.Activation ofthis
$ receptor by gçst o l
ylqh ine(which bindsto both g.subunits)induces
. ......- x
'
1 openingofNa+-cfkanné1s-->Na*influxanddepolarization.
@
'
ê'/vj
' *GA BA receptors:there are2 types ofG A BA receptors ip CN S'
. .
t.
j GABA
h .$rreceptorswhichopçpyw
.
çl--çllp.
. !!!
lt!sleadingtoCl .-influxand
tspsfî '
t yperpolarization,and GxbAy-receptorswllieh open K--channels
,-. - ... . . ...-..
'....--.. --.-
t also leadingto K efflux and hyperpolarization and may also lb
lo-ék-
) 2+
t C a -èhannels.
t
,i
t$
4,2.
7Gm kotein-linked receptors.
.
* 'Fhry are serpentine in sllape,m ade up of7 polypeptide loopsthat
span the cellmembrane(7 (yhelicalsegments).
Typeof G- Receptors &plf# trtinsdudion
Protein
Gs'
-Al
T?&%Lq=51
'n' U=Vr
receptors.
' Actlvation ofadenyl
-lda-receptors. cyclase and increase in
-D l-rece torja JI-A M P
Gi, -gzrreceptors. lnhlbltadenylcyclase
-$j
:
''>rr
- eceptofs.
..
>=GzD:- ,a
..
and decl-ease C- P,
and m ay open K jj
.
-5-1- 1'1l-receptors. -
j
-
th-receptors. :llAllllçls. - 4 . .-.. ..
Gq -ly-receptors . A ctvi at
ion o? l
.
-
&taandMu (excepton
. llos holi1seC and
bliE
;
.
oodves's
'el
ws). ,
increas2.
e,d DAG,
,c,,
,-4
111), ., ,-.,,
,
l-ll-receptors(exceptf)n
'- and Cy.
-.--2..
>
.. f
, -.
q.,: j
blood vessels). t''
t?t--'
r-'t7' ?-,
2'
-
5HTareceptoré. -- - - - - .- - - .- . - - - .
WhiteKnightLove
3-Tvrosine kinase-linked receptors: x-- -..- -

, ''.
. se
Exam plcs include:grow th horm one aladtinstllillq'(. .
recelltors.
. w
lnsulinreceptorsaremadeupoi-i'
isubunits(domainsl:2(4subunitson
thecellmembraneand 2psubunitstransfixingthecellmembrane(see
endocrinepharmacology).
T DNA-linkedintraeellularreeeptors (Geneaetivereeeptorsl:
z.... ,
clcpu-l .- steroid hormonesandvitalpjnD receptorsarefound inthecytoplasm
-.
.î
:;
.2.7'h@'f'':y.
u .. y. .> w''
.
.; '
w,., . u.
whereasfl/y-roid- -ho
.---.------------,
rmo -
------..-.---.----.------.p
-- .
- - u
qy-:-r
--.:j
.
?)%
-t-
pr
.sarepresen-.tinthenucleus.
',
-:- ' $,,17 c
(.
y--.- --Thé-
y-regulate gene transcrlption,translation Otm -RN A , and protein
.'b...;q
'c.
''
'':.X' synthesis> thatiswhy thehaveslow onsetofaction (seeendocrine
pharmacology).
B-pharmacologicalActions'
.the actions ofthe drtlg m ay be:
(
'-hlwoealactions(alsoknownastopicalactions)wherethedrugactsatthe
y.
.
slç
t ofapplication,e.g.
# .=...wv&- -w- - w,.om.ww -
skin oi
$
ntm entsand eye drops .
'-
tl system icactions:thedrtlg reachesthesystemiccirculation and is
..
bistributed to differèntsystemsasCNS, CV S,respiratory system ,etc.

'-- --.--
t'jl
'w.VRe
'.n
...
flexactions(alsocalled remoteactionsl:e.g.drugsthatelevate
4Z @ 7'XCFi111bloodpressureasNàradrenalineleadto''reflexbradycardia''
ï.
> throtlgh vagalstim ulation.
r #y
L
WhiteKnightLove
tluL; TW
DosageofDrugs(#taA't?/t?g# .
'
*Therapeutic D ose.
.ltis the dose required to achieve therapeutic effectin
anadulfmaleofaverageweight(70Kg.).
wLoading D ose:ltisthe dose adm inistered atthe beginning oftherapy in
acute conditionsas acute heartfàilure to reach the steady state plasm a
concentrâtion (Css)rapidly.ltistlsuallya largedoseand itlnay lead to
toxicity '
ifapplied to drugsw ith low therapeutic index as digoxin.
Loading dose (LD)= VdX Css

*klàintehance D ose:ltis dose given regularly t()m aintain Cssand is
equivalenttp theam ountofdrug elim inated.
M aintenancedose= clearanceofthedrug(Cl)X CssX Doseinterval(T.)
Maintenancedose(M D)= ClX CssX Tm
N .B.:
l-'l-hesmallerthedose interval(-I'm),thesmallerthe maintenancedose.
2-ln case ofIV infusion there is no dose intervaland the m aintenance
dose= lnfusion rate = ClX Css
3-clearnce(Cl):itisthevolumeofthebody fltlidsclearedfrom thedrug
in a unittime,measured in mL./minute(thevolumeofbody lluidstiom
which thedrug is rem oved by m etabolism and /orexcretion in a unit
time).
Clearnce = constantot-elim ination X Vd
C1= KelX Vd
C1= 0.693 X Vd
t1/2
*Minimalelfectivedose:thelowestdoserequiredtoproducea
therapeutic effect.
*M aximalTolerated D ose. .ltthe m axim tlm dose thatcan be safely
adm inistered w ithoutinducing toxic effeets.
*MeclianEïectiveDose(1'f.?é42
)..ltisthedosethatinducesaspecific
tlzerapeutic effectin 50% ofexperim entalaninzals.
*liedian ToxicDose(7D.
.
jpX Itisthedosethatindtlcesapartictllartoxic
effectin 50% ofexperim entalanim als.
/7j
wM edian LethalD ose /1.
- -/.,)ltisthedosethatilldtlcesdeath in50% of
..
experim entalanim :ls. '

wlherapeuticIndex. .= LD 5()/EDs().ltis a m easure ofdrug safety;the
higherthe index the saferthe drtlg.
WhiteKnightLove
FactorsA#'
ti#/#/z7
g the.
Dt)s'
candAction ofDrugn
(
''
/'
-.,1gc.
.
* lnfants(youngerthan2years)andchildrenrequiresmallerdosesthan
adults due to:
1-U nderdevelopm entofhepatic m icrosom alenzym es .
2-Low erlevelofplasm a proteins and low binding capacity .
3-Reduced renalexcretory function .
4-lm m ature B .B .B. ,..J.y).,'y

..
,..
2
:
...V
ft ) ,.
.
'
crJ?-N.B.som edrugsasdigitalisarerapidly ntetabolized in children than in
'
...- -.. -.
-. ''----'' ''''''' ' '' ''
àdultsand accordingly they neetf-highéfdbses(children aremoretolerant
to digitalisthan adults).ya(
l'r,'
a?>',#
* lnfant'sdoseiscalculated according to Clark% f'
t?lrzaz//t7.
' .
Infantdose =AdultdoseX weiRhtinpoundsorkveightinAk

:h'r; 150 yj '.s l 7o o, -csyet .
'N .
'
z. Child dose iscalculated according toTtiz/zlg'bkn
.
xll.
lnula...-sks
-
szs - -
Child dose zua dultdoseX Age in l/etzza - ,:'

:7
,.
'','
.e'VC
'
Age in yw zr, s 4 12
*child dose can also be calculated according to Ltillinz's Form ula:
Child dose = Adttltdose X a4yr, in y'etar,
y
20
a l
* * -1hedosecan beplsocalcqllAs-
d by thepercentagcmethod:
-
Age Percentofzztihtlt
o ose
1 m onth'
. 10% .
1 year: 2510.
3 years: 331$.
7 years: 50$$.
12 years. '
75% . >'
!
J,
X . L-n'
-
X 1fU
W '.
. Elderly'between60apd70Ayarsmjpty l2q0ftheadultdoseandthose
-.
over70yearsrequirett/lrb'fth
,'Je
-'sadut
--
ltq'àùsedueto:
1-W eaknessofhepat1c
''-mi
' crosomalenzymes.
2-Reduéed renalexcretory functions.
X-m odv Weight.. f
j/
' x':.
*'
l'
he m orethe body w eightthelligherthe dose exceptin casesofedçpl. l.,.4 trî.-.6.n
z j ',
..
a -. Wl' 'lg#(s 'C..,.M ..V'
1. cc/
'
'
v. ' H
or--f
ptwhich arenottaken into cpnsideration. . y.,u.
, '
8?
-f.
. :.t-, I
1!
'
v z'
-.
'
'>.
&.-- -* . .
,
013
.csvz'patientsdue to éxceskive btldy l'
atjpctèayk the:dosç of . .
..
- t
(?v,
.,
liop/lilké'drujsandreducethatotl''
ydi
'ojhilkc.ttrugs. '''
,x,
7t'p, ? 3-Botlv usbr/- tzcp Area..
.z
Thisisa'
tïz
ribr
a.xxi
...Acqllptemarameterforcal
.culationotwdosesthanageand
body wei* ght
T%vrwJand
j%-%-i
=tc
'v'
an
''.be
> obtained tw
rom speuific charts .
Infant's dose = A dultdose X illfant's spyface area

1.73(Adultbodysurgacearea= j.ysmz).
WhiteKnightLove
@&
;''I
. .;l
'x ny .
tz'Jo,
., .
ç
'
f-* t:l -' Q' -..
-,
-
,
).o.
.
4 Sex (Gender):
- kw
, c,xrp -hcwc;
* Fem ales.usually require sm allerdoses than m ales ofthe sam e ag
becatlse: 1
!
1-Femalesexhormonesarehepaticmicrosomalènzymeinhibitorsv v uchc-cen/yéwv,'-,r: -
w hereasm ale sex horm ones actas inducers
.
.
. ,--------. -..'
2-Fem ales ,
contain hlgherbody fat '?p ,-..lvz,) .
. '
.
.
,
t
t.f *- specialsituations in fem alesr- kv'.
..-.
4;.-.l
<? *
.. D
....xul
'.
<.
' 7f
:
i.ng
-
'a
-- /r'...'m
..-- -.
'.
-- .çn
-.
-ç-lg-atiqn avoid drugsthatm ay causebleeding asaspirin
'-'''-' .
.
- and êâgt
'
..
b- /
---------- .
z-.s.-.-nrrl
pi
xrt:.r.r:
- l.
j .
IïïLqj)b. .go-
?.-. 4- ,- :#'g-.-....-..--,L; rjp(uJq
.
- c-t
:oq-tf
... ... -
oaslr-
j
..
v
.
w'
wwweu.
- --.=s..,a .....,
....----v,
.-..
.. c
. .
.'''.
<.
. -2--.D,
''--
'
-7''
tl''
r =
lngPrejnancyaVOidter.a ...
t
-
,-
o
.
-,
.
-
ge
--
.
--.
-
l
.
ll;
-
c
--.dr
. ...ugs -.-
..-(
.-
.:
..
a -s
.--.a -spirin,cortisone, ACE fvv.s,pcms-y ,. s
jaj....sp
idlïi-bl
p 2t?o
r?ïr
'v -.z : krjt-
..
,.
. - . Gcvc
*' l
lzlnee-mecllzlne)' and titèrlnè Wl mu l ants(oxytocl
c drugsas '- , .
Cdrgot
'alhlne, PG analogsasm isoprosto ). .........- -e
uw.isgw
ruqFsà: .. . .
sf
.
c
.
s..
o
. '
3- 'fffir
-fg-'lactation avoid harm fuldrtlgs excreted in breastm ilk as
chloram phenicol,antithyroid drugs, m orplline,and oralanticoagulants.
s-Route ànl Time ofyjdm inistration:
* Oraldose ishigherthan parenteraland S L.dosesto com pensate for .
firstpasseffect(GIT and hepatic).

@ S.C .dose ishigherthan I.M .due to Iess vascularity ofsubcutaneous
tissue com pared to skeletalm uscles .
*'l''he route ofadm inistratioh aftkctsthe action ofsom e drugsas

m agnesium sulphate.b.);.,--,' ?.
p-> ilq
'/
,l,
),'
oêJ..-., ts?t R?.-?kc.,cn/
t?
,-.
-.r>; 77 )-
.
/-/:::. -::7,h:k''-'' nt,
. - .
.-.
-
ltactsasacholagogue(in smalldose)and ls-
urgativ:(in largedose)if
given orally.
)tp.*-;,....
r.Itactfrasa-deh dm tin ggent(asi
nbarc
sb
u;t
knezg
sy
leeruz-colma)ifgivenrectallyas
.-
. , .
'
=- - -z
t' .l-oy, retentlon Cnem a.
;b()Mn-
/11' '
Jtactsas
.
an anticonyptsantand sk-eletalm usçlerelaxantifgiven by I.V.
cry.:.
.
infusion -.
-.
-.-...--..-.-...-....
-...-... u l
putr
,
y yr
.
rs
x,
@M ostdr. p, -
ugsarebettergiven orally befbrem ealsbecause thepresence of.
;jr.
t
JzhxjV'
< .
food m ay reduceabsorption,butirritantdrugsasNSAIl3Sare bettergiven
@RCl-IX Ca 1S.
. - c0 .u1T?,rz-
- r
1--
6- I'
olerance: 4.
yty,
*Definition:failure to obtain the ustlalresponse by the usualdose.
*1%ypes.
' jj), fpyg
.v
1 Con enitalwhich is either: -,
'
?
A'- R JCial.'negros are tolerantto the m ydl'iatic action ofephedrine .
B-SPçcjes:yqhbitj- ar
.- -- ..-- ..
a
etolçrantto the system icactionsofatropinedueto
- - -- -
t-
''---t
>
hep
-
resehceofatro'pi
-
ll
o-
èmoy
es
uf.
i.r
./
ç
afse(attopi
*
nase')intheirplasma .
- lndividual:thisis ueib géii

-é-
ik variations.
-
j- c uited:longuseofdrugsasmorphine,barbiturates,nicotine,ethyl
r,
v,!2. Q' a1cohol,and amphetam ineleadsto acqtlired tolerance which isusually
t reversible,and may occurto som e-notall-actiollsofthedrug (see
morphine).
N
f
.
l
!t
''
-
',k-
WhiteKnightLove
':,ecausesofacquiredtolerance:
-
il-pharmacpkiluç-tigr s:HME inducersasnicotine and barbiturates
-- - . -
incr
.-.ease
. thei
g row n m etabolism .
- .
;cz'
JfTJ. 'y'
'Tz: .
z-pharm acodynam
xr'euGY'Fk !R*.?N g*guses:long
a
v useofdt tuxegs
' l eadsto ''down-re ul
.
ation''
< -v ..
2 *M-'*
S'yv
.
. ofrecep ktorsorde
l mu.6.
pt
a..
c.
n:,
u..
e t
o..przyy?';.
.,
,.
i q p of e n dog e
kkjj.rs:,ua....- m...-...... ..,.,.
nou s t
r a
.... - .,
.ns m
-
i
tters Ani alinsul
ln
i
nd
:
f
l.
'.
r
?
1
;
E-pxç
.
-
s
y.n.t
. sj
xy=
b.-o
...
d.y
..
''
.
-
'
f'
--
b-''
' r'-
- ma
'
-'
-'.tlo-h- v,
.
;.-y..
-.t,-z-
z
;'
z
.
p yr-
yaj
* Vpeciàftypesofacquired tolerance:
tL-
-
v r -fachyphylaxis'
r$'
-
t
?
.acuteacquired tolerance('see effeet0fephe%dr
:1
ineon -
' ABP). ,'ï. î
' -t
:
.
7
1%
'
,-A...-
..'q. '-
c. .scj-m ;d
yvu
- f rosstolerance'
.occursbetween drugshaving sim ilareffects asm orhine, -
barbiturates,orethylalcoholwith generalanaesthesia(allareCNS
#'
.
.
C1.
1
!1
7
ï
)
41
;t%
,
u 1P 1i,;,i-!';ûp
..,. .
;
)
.
'-
F
:.
,
-,
'-'
.
t
h
;
--:.
'..
-,-
.
-
.
7-D ependence:ltiseither' .
A -Psychic dependence = l-labituation:sudden cessation ofthedrug does
notcatlse w ithdraw alsym ptom sbutm ay cause em otionaldistressfora
shorttim e,e.g.m ethylxanthine beveragesastea and cotxke .
B-psvchic and Physicaldependence = Addiction:

Sudden cessation ofthe drug leadsto severe -and m ay be fatal-
w ithdraw alsym ptom s ''A bstinence syndrom e''w llich are the reverse of
thedrugactions,e.g.opiates(morphine,heroin,and codeine),ethyl
alcohol,barbittlrates,and nicotine.
8-Stp ersensitivilv zzqntolerance:ltisan exaggerated norm aldrug
response.ltis due to upregulation ofreceptors,dtte to inhibition of
m etabolizing enzym es,ordueto diseasesasthyrotoxicosis(see
adrenalinè).ltrequiresreduction ofthedose.
9-H vpersensitivi;v = A llergv:
,
'
*ltisan abùonnalunpredictabledrug response dtle to antigen-antibody

reaction(thedrugorametaboliteactsasal1antigenorbindstoahapten).
*1tdoesnotoccuron the firstexposure t()the drug which sensitizesthe
patientbutocctlrs on subsequentexposures,and isnotdose-dependent.
lManifestations.skinrash-udicaria-pllotosellsitivity(skinrashon
exposureto stln-lightl-asthnaa-angionetlrotic ed
.ema-anaphylactic shock-
bonemarrow depression(blooddyscrasias)bychloramphenicol,
sulphonam idessdipyrone,and thioam ide antitllyroids-cholestatic hepatitis
andjaundicebyclllorpropamide,testosterone,chlorpromazine,andalpha
m ethyldopa.
*crossallergy occursbetween drugshaving the sam e chem icalstrtlcture
assulphoàam idesand thiazidediuretics,orbetween drtlgshaving the
samçmechanism ofaction asaspirinandotherNSAIDSinastllmatic
patients.
10-Idiosvncracv:
ltis an 4bnorm alunpredictable drug responsedue to genetic detkcts.
(
4k*
. J
WhiteKnightLove
D ru s Idiosyncratic reaction
Succinylcholine: . l-stlccl
Vnylcholine apnea
' in patientsw ith
pseudocholinesterase deficiency .
' z-M alignanthypertherm ia
H alothane: M alignanthyperthetm ia . .
Aspirin-Primaquine- Hemolyticanemia'-l
JnpatientswitjA
'
Phenacetin- deticiency ofG w 6-PD.
Sul honam ides:
tsoniazid-Hydralazine Peripheraln-
etlritisin slow acetyi-
ators.
Hydralazine'
. SLE-like syndrom e'Xm**slo
w acetylators.
* Corticosteroids. .
ElevatelOP andinduceglaucoma
11-Pathologicalstate:theaction ofthedrug oceursonly in the
presence ofpathologicalconditions, e.g.aspirin lowershigh body
tem perature to norm albutdoesnotlow ernorm albody tem per
(aspirin isan antipyreti ature
cnothypothermic).
12-A' zpti//tpz/tz/state:
To distinguish between the realpharm aeodynam ic etïkk:tof
th a drug f'
rom
epsvtholoaicaleffed;a ''Placebo''isused (dtlmmy medication made
ofan inertsubstance asstarch orsugar) .
I3-cum ulation..
ltoccursw hen the rate ofdrug adm inistl-ation exceeds the rate of
elimination(bymetabolism andexcretion),e.g.cardiacglycosides ,
especially digitoxin,and guanethidine ltis m ore Iiable w ith drtlgs
.
following zero orderkinetics(see later) .
l4-l-lruz-Drug Interactionst/)z,l/g Combinationsl:

W 11e112 Orm ore drugsare adm inistered togetherinteractionslnay Ocetlr
p
which are eitherbeneficial(e.g.thiazidediureticsarecombined witlzK+-
sparing diuretics),orharmful(e.g.loop diureticsand am inoglycosidesare
ototoxicdrugs).
l-pharm acoceuticalinteractions'
.
They occurbefore drug adm inistration as during drug fbrm ulation

(Calcium saltscausechelation oftetracyclinesil4capsulesl-mixingof
drugswithIV fluids(Calcium saltswithNal-1CO3)-lnixingofdrugsin
thesamesyringe(Protaminezincinsulinwithsoltlbleinsulin).
Il-pharm acokinetie interactigps:
l-A bsorption:antilnuscarinic drugsasatropine and propantheline
increase absorption ofdigitalis-antacids decreasesabsorption of
38
WhiteKnightLove
tetracyclines,digitalis and AC E inhibitors-cholestyrallainedecreases

absorption ofany otherdrug ifgiven concom itantly
z-
bi
D istribution:a dnlg m ay displace otherdrugs from. theirplasma protein
nding sites leading to toxicity, e.g.N SAID S asaspirin and loop
diureticsas frusem ide displace w arfarin catlsing bleedi
di ng,quinidine
splacesdigoxin leading to digitalistoxicity
.
3-M etabölism 'HM E inducers(asnicotine,phenytoin
.
, barbitutates
rifam picin, ànd androgens)increaseelimillation ofdru gsmetaboliz,ed by
t
hheseenzymeg;whereasHM E inhibitors(ascinaetidille, fem ale sex
orm ones,chloram phenicol, erythrom yein, and grape fruit)reduce
clearance and m ay catlse toxicity .
4-Excretion:quinidine and verapam ilducrease renale

xcretion t)fdigoxin
and probenicid decreasesactivesecretion ofpenicillin(prolongsthe ,
adion ofpenicillin)andthiazidesand loop ditlretics(antagonizestheir
diu
retieaction).
lll-pharm acodynam ic lnteract
jons:m ay lead to:
- - -
l-A ddition = Sum m ation:theresultof2 active drug

s given together
equalsthealgebrïcsum oftheirindividualactions(1+ l= 2) .
z-
m
potentiation:theresultofan activedl'tlg with anallnostinactive drug is
b orethan theaction oftheactivedrug alone(1+ 0 hl), e.g.eaftbine and
arbtturàiespotentiatetheanalgesiceffbctofaspirin
3-synergism :the resultofadding 2 active drugsism.ore than the algebric
sum (1+ 1>2),e.g.rifampicin + isoniazidinT B.and penicillin +
.
aminoglfcosidesinseriousinfections.
4-Antagonism :which m ay be:
A-pharmacoloaical:agonist+ antagonist;itmay becompetitive(as
acetylcholine+ atropine, adrelzaline + propranolol noradrenaline +
,
prazosin)ornon-competitive(noradrenaline+phenoxybenzamine)
B-phvsioloaical:2 differentcom pounds acton 2 differentreceptors.
èausing 2 opposing actionsas adrenaline and histam ine .
C-chem ical:chem icalantacidsneutralize excess11Cl, and protam ine

sulphateneutralizes excessheparin .
5-* Reversalofaction:Adrenaline reversalafteralpllal-blockers.

N .B ..''D rug-Food interactiont''tyram ine found in yoghourtaad cheese
.
leadsto hypertensive crisis in depressed patientstreated by M A O

,
inhibitors(cheesereaction).
l5-* Biologicalvariations.
F undam entals ofwpharm acokinetics

Plasma /7t7//-//'/) time = t1/2.
'
*ltisthe tim e needed forthe plasm a drug concentration to be redueed by
50% (tlletimeneededtoeliminate50% ofthedrtlg il1plasma) .
WhiteKnightLove
*1tisconstantfordrugsfollowiny ''Firstorderkinetics''butisvariable
fordrtlgsfollowing ''Zero orderklnetics''(seelater).
*ltis used to estim atethe tim e needed to reach the ''steady state
concentration = Css''ofdnlgs follow ing tirstorderkinetics:
Cssisreached after4-5 t1/2 .
F irsttlp#cr kinetics and Zero order k-inetics:

Firstorder kinetics Ztdrtaorder kinetics
1-A constantpercentage (%ltfractlon- l-A constantamountornumberofmoles
proportiofl)ofthedrugiseliminatedin ofthedrtlgiseliminatedintlnittime .
tlnittim e.
2-The elim ination process is proportional 2-The elilnination process is fixed and is
to the drug plasm a concentration Drugs .notproportionalto the drug plasm a
w illreach a plateau w ith repeated doses concentration.D rugs do notnecessarily
.
reach a plateau w ith repeated doses .
3-constantt1/2 w hateverthe dose 3-v ariable t1/2:itincreases asthe drug

.
4 concentration (dose)increases.
l-inearkinetics:linearlog.
-
zl-Non-linearkinetics.
concentration-tim e curve.
Q
J
L
tt
xw-
qs'Yj
'-j--ipm.-
s-N on-saturable kinetics:no enzym e s-saturable kinetics:saturation ofthe
saturation occurs. fnetabolizing enzym e orthe carrier
transporteroccursw ith high
concentrations.
6-ltess liable to cum tllation and toxicity. 6-l-iable to cum ulation and toxicity.
'/-M ostdrtlgs obey firstorderkinetics. 7-li
ïxam ples ofdrugsthatfollow zero
Orderkinetics:large dosesOfaspirin-
pllenytoin-alcohol.
(Smalldosesofsuch drugsfollow first
orderkineticsas the enzym esare not
#atuVYC2 yV!-
),
.
-#l
.
' .Al
soabsorptionfrom sltprepalutions,depotprep-ar-s.,ol
atl---l
.s
--
as-S--
c .--
im plants,and transdermalpatcheslbllowszero ordel'asaconstant
am otlntisabsorbed in a tlnittilue.
40
WhiteKnightLove
AdverseEffectsandToxicitvofD rugs ,
A-unpredictableadverse effects..
l-A llergy. z-ldiosyncracy.
B-predictableadverse etfects.
.
l-side effbct:unavoidable action ofthe drug notrelated to the dose, e.g.
atropinecausesdry m outh.
z-secondaty effect:e.g.prolonged use ofbroad-speetrum antibiotics
èspecially ifincom pletely absorbed orally'causes stlperinfection and
vitam in B and K deficiency .
3-o verdpse:e.g.hypoglycem ia dtle to overdose ofinsulin .
4-l-lepatotoxicity:e.g.by halothane .
s-N ephrotoxicity:e.g.by am inoglycosides .
6-N eurotoxicity = N erve dam age'e.g.ototoxicity by am inoglycosides

.
and loop diuretics.

7-rreratogenicity.
s-Bonemarrow suppression(blooddyscrasias).
g-rrolerance,dependence,and addiction .
lo-lntolerance(supersensitivity).
ll-latrogenicity:drug-induced(physician-induced)disease;e.g.aspirin
causesljeptic ulcer,alpha m ethyldopa and reserpine cause parkinsonism .
lz-carcinogenicity:bytoàaccosmoking.
13-Drt1g interactions.
* Adversedrug elfectsarec/tvxx//zc//into:
TypeW =predictable undesirablesidee//-,c'/A'..
lnclude:side effects- overdose toxicity - Stlpersensitivitx - Secondary
effects- Cytotoxicity(hepato-,nephro-,neuro-toxicity)- Drug
interactions.
TypeB =unpredictablesideeyects.
lncltlde:Hypersensitivity and idiosyncracy.
TypeC L
uzchronicetfects:
lnclude:Tolearnce and dependence - latrogenicity.
TvpeD =L
D e/qpe#eyects:
lncltlde:Teratogenicity - M tltagenicity --Carcinogenicity.
TypeE '
zœnd ofuse effects:
lnclude'
.rebound effectaftersudden w ithdrawalofclonidine and beta
blockers- acute A ddisonian crisisaftersudden w ithtlraw alof
corticosteroids- withdrawalsympton'
ls(abstinencesylldronle)inaddicts
to m orphihe,heroin,alcohol,barbittlrates,tobacco...
41
WhiteKnightLove
D rugs in G eriatrics
, '
k (GeriatricPharmacology)
A snoted before;elderly patientsbetween 60 and 70 yearsrequire 2/3 of
theadultbose,andthoseover70yearstequireonly l/2oftheadultdose .
Thisisbecapse ofthe follow ing changes:

A-pharm atokinetic t?/cz??2gt?5'.'
l-A bsorption:therate ofabsorption is slow erbuttlte extentisusually not
affeded.This is because of:
-
delayed gastric em ptying.
-
decreased blood tlow to GIT.
-
impaired lntestinalm otility.
-
elevated pl-lofthe stom ach.
z-D istribution:
-
reducedlean(muscular)body mass.
-
reducedtotalbody water(Vuofwatersolubledrttgsasparacetamolis
reduced).: .
-
increasedtotalbodyfat(Vaoftàtsolubledrugsasbenzodiazepinesis
increased).
-
decreased serum album in w hich leadsto increased free fraction ofdrugs
which m ay cause serious adverse eflkctsas warlitrin , btlta-acid
glycoprofein is increased.
3-Elim inationa.
M etabolism '.the hepatic blood tlow is reduced and the activity ofH M E is
decreased(phaselreactionsaremoreaftbctedthallphase1l)
Renalelim ination:renalexcretory tknction isdecreased w ith age and
reduces elim ination ofm any drugs asdigoxin,l-lz-blockers,and
gm inoglycosides asstreptom ycin.
B-pharm acodvnam ic changes.
.
-
Decreased receptorsensitivity asredtleed l'esponseto jl-blockers.
-Exaggerated response to CN S depressalltdrugsas allalgesicsand
hypnotics.
-
lncreased risk ofposturalhypotension (may bedtle to disturbed
baroreceptors)andthatiswhydrugscausingposturalhypotensionare
betteravoided.
Otherproblemsingeriatrics:
l-polypharm acy:m ay cause seriousdrug interactions,so itis advisable to
usem ipim alnum berofdrugs.
WhiteKnightLove
z-Disturbancesin memory,vision,and hearing wllicllim pairs

com pliance.
D rugs in Pecliatrics
D iïerençes:e/
. wepnpediatricstz/tt/J#l///-&'
l-luargervolum e ofbody w ater.
z-laow erbody fat.
3-Lessplasm a proteins.
4-l-essactiveHME (lessabilityto coqjugatedrugsaschloramphenicol
leadingtotoxicity = gray baby syndrome).
s-laessm ature BBB,i.e.itism ore perm eable to drugs leading to CN S
toxicity.
6-taessefficientrenalclearance w hich m ay be partictllarly dangerous w ith
am inoglycosides.
'7-M ore tölerantto som e drugs asdigitalis and * atropine.
8-A m phetam ine and ephedrine cause sedation in children butthey cause
CN S stim ulation in adults.
WhiteKnightLove

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GEN ERA L PH A RM A COLO G Y

Pharm acokindics include:

VLIndications = Therapeutic ?/-$'d.$'

* Itisobviousthatabsorption from any site(GI'r lung,skeletalmuscles,

5-Pinocytosis'.itisan activeprocess(energy-dependent)in wllich the

Drug llm ization:

6-lonization Constant= pKaa'itisthe p14 ofthe m edium in w hich 50t% 01: -

Thism eansthatatpl-l3.5,50% ofaspirin isionized alld 50% is

pKa= pl-l+ log.Unionized fbrm

pK a= pl'l+ log.lonized tbrm

8-The sam e rulesare applied to renalexcl-etion 01'drtlgs:allkalinization of

A -Factorsrelated to the drtlg:

1-Lipid splubility and lipid-w atetpartition coefficiellt:them ore the lipid

I.V .in case ofshock.

*lk-ood decreasesabsorption ofanlpicillill.

2-FJI?/ Cbmpartm entM odel.

# A spirin >nd sulphonam idesdisplace sulphonyltlreas leading to

lsulphoùam ides displace bilirubin frotn plasnaa proteins,which increases

OCCX W itl)!therapeutic doses

llwipid solùbleunionized drugscan penetrateB.B.B.and exertC.N .S.

l-passageithrough breastm ilk:

ofitshigh lipid conentand rich vasctllarity,thentlley areredistributed

allow sm eàsurem entofthe totalam ountofthe drug in the body:

* ,rhçlaim ofbiotransform ation reactionsisto ,,convertjjpopjjjjjc

4-V ely rarely;a t

M içrosom alEnzym es N on-M icrosom alEnzym es

3-u%x Getlder . '

ln cases o starvation,there is m arked depletion of.glycine contentwhich

l-K idne Renalexcretion ..

orvitamipiC (ascorbicacid)promotesexcretjon ot-basicdrugsas

increasin theirexcretion in urine through changing the pl-lOfurine.

Som e druIsexcreted by bile m ay undergo yjentero-hepatic recyclejjwhich

D -lLar e ntestine Stools : drtlgs thatare poorly absorbed orally as

3-Respir tol ,$'stem .inhaled generalanaesthetics,w hethergasesas

l-sweat. ery few drugsare excreted in sw eatqsrifam picin and 1312.

*G ive Re jon Ex lain .

Routes t?/'p r/zf A dm inistration

R ollt The drug A tlvttntttges UD -

; Freely you have received; freely give.

C-Rectal: ln the form of Can be used iforal l-inconvenlenttbrm ost

B-I.M .. l-soltltions. Rapid onsetand l-A void highly irritant

3-lnhala ion G ases-v olatile l-llseftllfor * lrritation ofbronchiby

powder(given z-very rapid onset

l-used fbrltx al Undesirable system ic

*o ther outes o A dm inistratlon:

llntra-p ritoneal.in peritonealdialysis .

llntra-th cal:in spinalanaesthesia and in treatm entofm eningitis .

thç form fa solid capsule(pellet)implanted undertlleskin,from which

*How t ,rolon the duration ofaction ofdrttgs .

l-D elay bsorption by:

4-D elay r nalexeretion e.g.by adding probenicid to penieillin.

bo# tt. g j A -M echanism ofad ion. .

M echanistn ofaction ofJzw#x.'

7-A ction on Receptors:

drug action. -Adre''''vnaline(agonist)andpropranolol

m embrane(e.g.(z-and p-adrznergicreceptors,and muscarinic and

* D rugs Acting on recçptors are classified into:

1-A GtlN fuîtF,.

MExam plesofagonists:A cetylclltlline-A drenalille-N oradrellalille.

Z-AN TA GONISTS = BLOCKERS:

efficacy''ofthe agonistlog.dose- response ctlrve.

duration becauseitisrapidly nwtabolized,e.g.succinylcholine(non-