'It is more blessed to give than to receive.

1y
P hqrm açologv ofB lqoJ

WhiteKnightLove

C'W ''

y ')
4
.
 Freely you have received; freely give.

Thischapterdealswith //ct?Jt
. '?//t?w?Wg drugs..
l-H em ostatics and C oagulants:D rugsused to stop bleeding.

ll-A nticoagulants:D rugs used in prevention and treatm entofthrom bo -

em bolic diseases in vivo and are pal-ticularly effective in venous

throm bosis.They are also used to preventblood clotting in blood samples
andduringbloodtransfusion (invitro).
#

lll-Antiplatelets(AntithromboticslzDrtlgsused to preventplatelet
aggregation.:They are pal-ticularly effective in prophylaxis againstarterial
throm bosisas coronary throm bosis causing acute nayocardialinfarction.
N LB...arterialthrom biare fon- ned ofplateletaggregation m ainly and are
thus ltnow n as ''w hite''throm bus, w hereasvenousthrom biare form ed of
fibrin m ainly w hich entanglesR BC S and are called ''red''throm bi A part
.

ofvenousthrombimay detach folnningan embolus(floating thrombus) .

lv-Fibrinolytics(Thrombolytics):Drug.susedto dissolve(lyse)already
formed thrpm biand em boli,m ainly arterialthrombiasin acute
m yocardialinfarction due to coronary throm bosis.

V-Antihyperlipoproteinem icDrugs(Antihyperlipidemics):Drugsusedin
treatm entofhypelcholesterolem ia and /orhypertriglyceridem ia.

I-H em ostatics and Coagulants

.
A-LOcalHemostatics(stypticsl:
l-physicalmethods:application ofpressure(compression),cold,or
cautery(e.g.by diathermy).
z-v asoconstrictor druo
ms asadrenaline and ephedrine locally in cases of
epistaxis(corltraindicatedinhypel4ension and bleeding from t'
ingers,toes
andduringmalecircumscision).
3-A stringents as tannic acid and alum ,w hich precipitate surface proteins
atsitesofbàej
eding.
4-taocalcoagulants to stop bleeding from m inute vessels:
a-Throm bin and thronnboplastin.
b-l-luman fibrin foam (sponge)used in surgery.
c-A bsorbablé gelatin sponge.
d-oxidizedcèllulose(oxycel):surgicalgauzewhich actsmechanically
butshould '
notbe leftfor long tim e asitpreventsepithelization,
WhiteKnightLove
'It is more blessed to give than to receive.

Thl'
schapterdealswith //Jt?following drugs:
l-l-lem ostaticsand Coagulants:D rugstlsed to stop bleeding.

ll-Anticoagulants:i3rugsused inprevention andtl'eatmentoft

'hrombo-
em bolic diseases in vivo and are particularly effective in venous
throm bosis.They are also used to preventblood clotting in blood sam ples
andduring bloodtransfusion (in vitro).
A

lll-Antiplatelets(Antithrombotics):Drugsusedtopreventplatelet
aggregation.:They are pal-ticularly effective in proplnylaxis againstarterial
throm bosis as coronary throm bosis causing acute m yocardialinfarction .

N .B ..'arterialthrom biare fon-

ned ofplateletaggregation m ainly and are
thusknow n as ''w hite''throm bus, w hereasvenousthrom biare fol-m ed of
fibrin m ainly w hich entanglesR BC Sand are called ''red''throm bi. A part
ofvenousthtombimay detach folmaingan embolus(floatingthrombus) .

lv-Fibrinolyjics(Thrombolytics):Drugsusedto dissolve(lyse)already
fonned thrjm biand em boli,m ainly al-terialthrombiasin acute
m yocardialinfarction due to coronary throm bosis.

V-Antihyperlipoproteinem icDrugs(Antihyperlipidemics):Drugsusedin
treatm entofhypelcholesterolem ia and /orhypertriglyceridem ia.

V l-A ntianem ic D ructs:D rugsused to treatanennias .

I-H em ostatics and Coagulants

A-laocalHem ostatics(stypticsl:
l-physicalmethods:applicatl
ion ofpressure(compression), cold,or
cautery(e.g.bydiathermy).
z-v asoconstrictor drugs asadrenaline and ephedrine locally in casesof
epistaxis(contraindicated in hypel-tensionandbleedingfrom fingers,toes
and duringmalecircumscision).
3-A stringents astannic acid and alum ,w hich precipitate surface proteins
atsitesofbàek
eding.
4-tvocalcoagulantsto stop bleeding from m inute vessels:
a-Throm bin and throm boplastin.
b-l-luman f'
ibrin foam (sponge)usedin surgery.
c-A bsorbabl: gelatin sponge.
d-oxidizedcéllulose(oxycel):surgicalgauzewhich actsmeclnanically
butshould '
notbe leftforlong tim e as itprevents epithelization.
WhiteKnightLove
 Freely you have received; freely give.

B -system ic Coagtllants:
l-v itam in K :
*1tisobtained from dietand is also synthesized by bacterialflöra .

*ltis a fat-soluble vitam in, so absorption is im paired in casesof

obstructivejaundiceandby liquidparaffin (lubricantpurgative).
*1tis reduced in the liverinto an 'active fon-n. Reduced vitam in K is
active and is essentialfor activation -by carboxylation-ofcoagulation
factors11(prothrombinl,vll,lX,andX,and ofanticoagulationproteins
C and S.A ftercarboxylâtion ofthese factors, reduced active vitam in K is
converted into inactive vitam in K epoxide w hich istransform ed again
into active reduced vitam in K by vîtam in K cpoxl
W c reductase w hich is ,

inhibited by oralanticogulants as w arfarin and by large doses of

salicylates(aspirin).
Vitam in K ----------* reduced active v/'
/4?'
7J/7cK -------#-Carboxvlation
1 . . . . .
(activation)ofcoagltlatlonfactors+ lnactlvp v//tppk/zcK cpoxlde.
Jzr//tzpcfn K epoxide reductase
J'
Zj//pz
zjn K cpoxf#c-------------------------------------1 reducgd Jc/jvc vt'tK .

t'
/n/cjAj/ct/by wtw-
. Jar
' in and Iargedosesofaspirin)
*v ital-nin K isthe specific antidote oforalanticoagulants .

*v itam in K is used in treatm entofbleeding due to hypoprothl-om binem ia

-

w hich is catlsed by:

D rug,
-
%..O verdose oforalanticoagulantsand salicylates.
-
Decreased y'pc//lt>/ys'ofvitam in .
/t-bv //(.
?/w.'Prolonged useoi7oralbroad
spectrum antibioticsespecially ifincompletely absorbed asampicillin,
A
cefadroxyl,and tetl-acycline.
-
Excessiven:c/tpho/àî/'
n ofvitamin K.
.Antiepilepticsasplnenytoin,
phenobarbitone,primidone(tpartially convertedintophenobarbitone),and
carbamazepine(a1lare1-1N11:-1inducers).
-
llecreaseds/nxta/-p//
bFcofvitaminK.'Liqtlid paraffin (decreasesvitala'lin
K absolmtion),obstructivejaundice,malabsorption syndrome,and by
drugs asneop ycin.
-llecreased z//s//ztzptnn ofvltam ln K 7n liver.
. .Liverdiseasesand neonates
especially ifprem ature.
'
t
z-protaminlsulphate:basic and electropositivedrug -chem ically
-

antagonizesheparin (which isstrongly acidicand electronegatively

charged)-specificantidoteofheparin usedto controlbleedingdueto
overdose ofheparin-givep lV .
WhiteKnightLove
'It is more blessed to give than to receive.

B -system ic Coagtllants:
1-'
V itam in K :
*1tisobtained from dietand isalso synthesized by bacterialflöra .

*ltis a fat-soltlble vitam in, so absorption is im paired in casesof

obstructivejaundiceandby liquiclparafûn (lubricantpurgative).
@1tis reduced in the liverinto an active fon-n Reduced vitam in K is
.

active and is essentialfor activation -by carboxylation-ofcoagulation

factors11(prothrombinl,vll,1X,andX,and ofanticoagulation proteins
C and S.A fter carboxylàtion ofthese factors, reduced active vitam in K is
converted intp inactive vitam in K epoxide w hich is transform ed again
into active reduced vitam in K by vitam in Jf epoxide reductase w hich is
.

inhibited by oralanticogulantsaswarfarin and by largedosesof

salicylates(aspirin).
Vitam in K ----------*'rcJâfcct;
/active V/Jt7PJ/'
Z?K ------->'Carboxylation
(activatlon)ofcoagulatlonfactors+ lnactlyev7/t?/77Tz7K cptn.
x/lc.
Vitam in K epoxide reductase
Zj/tppz
yjp,
zkm cpgxf#c-------------------------------------F reduced sc/jvc vitlc
.

(inhibited /7.)7warfarinand Iargedosesofaspirin)

*v itam in K isthe specific antidote oforalanticoagulants.
lv itam in K isused in treatm entofbleeding due to hvpoprotlu-om binem ia
w hich is catlsed by:
-
D r7?g.&.'O verdose oforalanticoagulants and salicylates.
.

-
D ecl,'etls'etly)?FJ//Jt?,
y/-$ofvital,
nin 1k-Avp'
/tn/-tzzyf.ll'ololnged use oforalbroad
-

spectrum antibiotics especially ifincom pletely absorbed as am picillin,

#
cefudroxyl,and tetl-acycline.
-
Excessivelnetabolisln o/-vj/cpzn/n K..Antiepilepticsasphenytoiln,
phenobarbitone,primidone(partially convertedintophenobarbitone),and
carbamazepine(a1lareI-IM E inducers).
-
Decreased tr?/n.çtn/-p/à//cofvitamin l/f.
'Liquid paraffin (decreasesvitallain
K absolmtion),obstructivejaundice,malabsol-ption syndrome,andby
drugsasneom ycin.
-
D ecreased z/p//ztzptnn ofvltamln K ln llver:Liverdiseases and neonates
-

especially ifprem ature.

'
y
z-protaminlsulphate:basicandelectropositivedrtlg-chemically
antagonizesheparin (which isstronglyacidicandelectronegatively
charged)-specificantidoteofheparinusedtocontrolbleeding dueto
overdose ofheparin-given lV .
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 Freely you have received; freely give.

3-A ntifibrinolytics:as Tranexalnic acicland Anlinocaproic acid w hich are

used to controlbleeding due to overdose offibrinolytics asstreptok-inase
Ie(seelater)
andalteplas .

A dverse effects:intravascularthrom bosis .

4-Throm boplastin lM .
s-Antihemophilicglobulin (AHG)IV intreatmentofhennoplnilia.
6-vitamin C in treatmentofscurvy.
7-Fresh blood transfusion.
8-Fresh frozen plasm a. '

g-A protinin:blocks plasm in,used forprophylaxis in cardiopulm onary

,

bypass sklrgery.

* Sclerosing tpq'
t-
?z?/,
s.'as sodium lrol-huate-syllnasol-sodiulqnricinoleate,
.

used to induce coagtllation,and penuanentobliteration ofvaricose veins .

Il-Ant+ lateletD rugs

(Antithrombot
)#
icDrugs=plateletAggregation.
lz?/cj/pj/tpr.
s)
Factors stl'm ulating aggregation Fsc/tlnçinhibiting aggregation

1--fhromböxaneAa(TXAZ). l-prostacyclin (PG12).

Z-A D P. 2-c-A M P .
3-Glyeoproteins(ac,
tonspec/ific 3-C-GM P.
G P11b/111a receptors on platelets
and stim ulkte binding of
fibrinogentoplatelets).
4-C aa+.

s-serotonin (5-l-lT).
6-collagen.

hfechanism ofact
jon ofzjntithl-qm botics..
- .

A -lnhibition ofTX A ?synthesis by ilnhibition ofTX A Z synthetase

.

(plateletCOX):
l-Aspirin (actetylsalicylicacidl:infantile(pediatric)dosesofaspirin (75-
- -
150mg./day)causeilrevelsibleinhibitionofTXA:by acetylation ofthe
enzym e.OtherN SA IDSare reversible inhibitorsand haveshoh dtlration.
Adverseeffects:increasesincidenceofhemorrhagicstrokes-bl
teeding (as
from GlTl-allergy.
z-D azoxiben:usually com bined w ith aspirin.
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B-lnhibition bfADp-deoeqçkntpathwav:thesedrugsinhibitbinding of
ADP to ADP receptorson plateletsand so inhibitactivation ofGP Ilb/llla
receptorsand inhibitbinding ofplateletsto 15brinogen and to each other.
Exam ples include:Ticlopidi
- neand Clopidogrel(ticlopidineanalogue).
They areused during stentinsertiön (* maximtlm effectafter3-5days).
Adverseeffects:bleeding(nospecificantidote).
Ticlopidine m ay cause neutropenii butclopidogrelissafer .

C -B lockers ofG P llb/lllq receptors:these drugs inlaibitbinding of

fibrinogen to G P llb/llla receptors on platelets and tllus inhibitplatelet
aggregation.They include:
Abciximab (monoclonalantibodiesofGP llb/llareceptol-s):
ug
Tirofiban -Epitifibatide.
They are given by IV infusion during surgery and catheterization
(* oraldrugsaretootoxic).
A dverse effects:bleeding especially ifgiven w ith anticoagulants .

D-prostacycliflanalocue:Epoprostenol(shol'tacting,given1V).
E-D rugs increasing plateletC-A M P:
D ipyridam ole -cilostazole -pentoxyphylline:inhibitphosphodiestel-ase
leadingtoiycreasedplateletC-AMP.
* D ipyridam ole is ineffective alone and isused in com bination w ith
aspirin.Italsoavasodilator(* coronary vasodilators)andmyocardial
stim ulantboth directly due to increased cardiac C-A M P and reflexly
follow ing kasodipatatiolqand hypotensiol).
Cilostazole and pentoxyphylline are used m ainly in treatm entof
intennittentclaudication.

Indications ofAntithrombotics:
Prophylaxisagainstthrolnnbo-embolisl'
n (especially arterial)in oldage,
stable and unstable angina,afternnyocal-dialinlttrcti01) anclcerebl-o-
vasculartl%om bosis.

Common adverseelfect:bleeding,nospecit'icanticlotè,blood
transfusion m ay be required.
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 Freely you have received; freely give.

111-F ibrinolvtics
#Anticoagul
lantsandantithrombotics(antiplatelets)areused for
prophylaxis cyfthrom bo-em bolism butthey have no effecton already
fonued throm biand em boli.
#Fibrinolylicsdissolve(lyse)alrepdy formedthrombiand emboli.
4M echanism ofaction.
- -. . .
Stimulateconversion ofinactiveplasminogen(pro-fibrinolysin)into
active plasm i
,n (fibrinolysin)which dissolves(lyses)already fonmed
thrombiand emboli.
klndications..
R ecently form ed throm biand em bolias in coronal'y throm bosis causing
acute m yocardialinfarction,cerebro-vascularthrom bosis, pulm onary
embolisln,somecasesofdeep venousthrombosis(DVT).
They should be given as early aspossible before irreversible tissue
damage(bettérresultswithin 3-6hours).
*ExamlpesofFibrinolvtics:
l-streptokinàse:
*synthesized by streptococciand is highly antigenic
' .
,

*stimulatestsystemicplasminogen (non selectivç)causing.high incidence

ofblteding.k '
*1tisgivenbyIV drip (for1hourandused within 4hours,noteffective
in olderthrombi).
*streptokinase doesnotdirectly stim ulate conversion ofplasm inogen
into plaslnin,itstim ulates ''pl-oactivator''into ''activator w hich stim ulates
plasm inogen conversion into plasm in.
z-urokinase:a hum an enzym e syntlnesized by the kidney ltism uch less
.

antigenic thatstreptokinase.
S-R ecom binanttissue Plasm inoeen A ctivator(r-tpA=Alteplase):
- ,

@1tisa protease enzym e synthesized by recom binantDN A technology so

itis m uch less antigenic butexpensive.
*ltbindsspecific4lly to localplaslzninogen bound to tsbrin ofthrôm btls or
embolus(clot-selective)soithastl4eadvantageofmillimalsystemic
bleeding. '
lshol-tertl/2 than streptokinase butm ore effective in older clots.
4-otherplasm inogen activators'.A nistreplase-Tenecteplase-Reteplase.
#Adverseeftects:
l-B leeding:m ore com m on w ith streptoltinase,and is treated by
antifibrinolyiicsastranexam icécid and am inocapl-oicacid.
C erebraland G 1T bleeding m ay occur.
z-A llergic reactions and fever:com m only w ith streptokinase.
3-Antibodidstostreptococci(duétorepeated infections)may inhibitthe
action ofstreptokinase. 4-M icroem boli. s-R e-perfusion an-hythm ias.
'
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6
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,
1V-A nticoazulants
1.....7
Anticoagulahtsare classitied into the föllowing groups:
A-A nticogulants zf-çcJ in vitro only.
- - - - . -

They decrease ionized Ca2+ in blood eitherbyprecipitatl .on as N a+ and K +

oxalate or11y de-l'
onl'
zation asNa1andK+citrate, andE-DTA They are .

used in blood sam ples and blood banks during transl

uilsion .

B-Anticoagulantsin vivo/7:/)/(= IndirectJc/2'F:,

$.'
They include oralanticoagulants w hich interfere w ith vitam in K
activation in the liver:eoum arin derivatives'w arfarin,dicuom arol,and
,

trom exan.

C-A nticoagulants bo// c/?7vivo t7/cl in vitro t-D/?-cc/actinz).'

-

'
l-D irectthrom bin inhibitors(DTls):hil-udin and lipirudin .

z-lndirectthrom bin inhibitors'

- .actvia activation ofantithrom bin l11and
includeheparins:unt-ractionatedheparin ItJ'
FHIand1ow molecular
weightheparin ILM W I2JI.
* A nticoagulants are classified clinically ihto:
l-paventeraltnn//'coags/D z7/ss'.'heparin-hirudin - lipirudin.
.

2-O raIantiqgagulants.
.w arfarin.

H EPA RIN S
J- Unh-actionated l.
Jcp?.?r//cIUFIT .
'
Alsoknownas''HighM olecularW eightHeparin''(HM W H).
*sol.
lrce.
.,
A nim alorigin'
.heparin is naturally presentin m astcellsw ith histam ine
and itisprepared from bovine lung and porcine intestine.
*C hqn-
. - i.
-qzw .

M ucopolysacèharide- strongly acidic(itisthestrongestorgallicacid).-

electro-negativel
y charged(acidityandnegativechargeareessentialfor
.

theanticoagulantactivity ofheparin).
*p harm acokinetics:
@A bsol-ption:heparin isnotabsorbed orally.
lRouteofadlwninistration:heparin isgivenIV (bolusand infusion)and
SC butneverIM to avoid hem atom a.
*D istribution:cannotpass placentalbarrier and is safe during pregnancy.
*Fate'
.heparinisrapidly clearedbyreticulo-endothelialsystem (RES),
m etabolized by the liverandpartly excreted unchanged in tlrine.
ltis notexcreted in breastm ilk and so itis notcontraindicated in
lactation.
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*pharm acodvnam ics:

>?.
& c,;?c??7.s??7of'
-
actlon:
H eparin activates ''antithrom bin 1J1''known asheparin cofactorw hich in
turn inhibitsthrom bin and othercoagulation factors as factorX a H eparin
.

is an indirectthrom bin inhibitor .

pharm acolozicalactionu
-

l-D irectanticoagulantcharacterizçd by the follow ing' .

Advantages:
#R apid onset:l-actsdiréctly on coagulation factors in blood
2-given IV or SC .
AA cts 130th in vivo and in vitro .

A'
N otcontrqindicated in pregnancy or lactation .

#N otliable to drug interactions .

D isadvantages .
.
A
#shortduration:due to rapid clearance by RE S .

AGiven only byinjection andrequirescarefulm onitoringofthedose(see

later)andaccordinglythepatientmustbehospitalized .

z-tzipemicctearing effect:reducesplaslnaturbidity afterfattymealsdue

to liberation oflipoprotein lipase .

3wAntiplateletaction (inhibitspl .ateletaggregation)in largedoses.

*controlofD ose. .
l-zqctîvatedPartialr/zprtpnclloza/tr
ps'//'
/cTime(aPTT):
-

-
No l'
mal:ajro
A fter hepat
ut30-40seconds.
in:should be 2-2.5 tim esthe norm alvalue.

l-clottinz Time (Coazulation timel:

-
N ol-m al:5-7 m inutes.
-
A flerheparin'.should be 2-2.5 tim es the norm alvalue
.

*z
qdverse effects:
l-l-lem orrhage îsthe m ostserious adverse reaction and itm ay occur from
any site as epistaxis,hem aturia,etc.Treated by:stopping heparin +
specif'icantidote(protaminesulphate)+ fresl:blood transftlsion.
z-l-lypersensitivity reactions.
3-Throm bocytopenia:w hich m ay be m ild transientreversible,or severe
due to heparin-induced plateletaggregation orheparin-induced
antiplateletantibodies.This m ay lead to ''paradoxicalt-
?pJ/7t?/?'-
$'??J''
.

H eparin should be stopped and directthrom bin inhibitors ashirlndin and

lepirudin are tlsed. :
4-* Throm bosis:chronic useofheparin reducesantithrom bin 1llactivity
leading to increased risk ofthrom bosis.
s-Transientteversible alopecia.
6-Transientreversibleosteoporosis(maycausespontaneousfractures).
7-l-lyperkalem ia:due to inhibition ofaldosterone release.
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tbReversalofaction:
l-stop hepatin.
l-protam ine sulphate is the ''specitic antidote''ofheparin:
-
1tisstronglybasicand electro-positively charged (actsby ''chemical
antagonismss),1mg.protamineIV reversestheaction of100 I.U heparin.
. .

3-Fresh blood: transfusion.

*contraindications:
l-l-lypersensitivity.
z-severe uncontrolled hypel-tension .

3-G 1T ulcerations' .peptic ulcer and ulcerative colitis

.

4-Threatened abortion .

s-stlbactlte bacterialendocarditis .

6-D tll-il'
1g and aftereye, brain,orspinalcord surgery, orlum barptlncture .

7-B leeding disorders as hem ophilia, tllrom bocytopenia,anclpurpura.

S-A ctive T.B .
g-lntracranialhem ol-rhage, headinjury,andbrai
n tumors.
lo-v isceralcarcinom a.
1l-A dvanced liver and kidney diseases.

11 -
Low M tolecular l
zrcïg/c/Heparin (L. f-
zr f?.
'
*Exalnples.
.Enoxaparin - Daltaparin-Tinzaparin .

They are obtained by enzym atic depolym erization ofU FH .

t
bzqdvant
ages over UFIL'
l-l-lighbioavailability afterSC injection and longdurationallowing
singledaily injection.
z-potentiate the action ofantithrom bin 1llm ainly on activated factor X
(Xa)andhavelesjeffecton othercoagulationfactors;sotlleyareless
liable to induce hem orrhage.
3-Equaleftqcacy asU FH .
.
4-predictable pharm acokinetics, so the doses are easily calculated 4 and no
need fol-naonitoring by aP''
1-T 7 and can l3e Llsed as out-patientthcrapy.

H't-
w tyrïn-/j/t'c anticoazulants lD
- .' irect F/?7,t?p'
7>/??Inhibitors D F/ls'?.'
.

l-H irudin:obtained from m edicinalleech.G iven by IV infùsion .

z-Lipirudin:chem ically related to hirudin butitis synthesized by

rècom binant'D N A technology.G iven 1V .
D T1s are indicated in patientsw ith heparin-induced throm bocytopenia,
and the m ain adverse effectis bleeding especially ifused w ith
fibrinolyticyasstreptokinaseandalteplase.
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* Fondapariinux:selective factorX ainhibitor-given SC once /day m ore

- - -

effective than LM W H in prophylaxisofvenousthrom bo em bolism as

-

Dv-fllongtj l/z-noneedtouseantidote(anticoagulationreversal)before
stopping (beforeneurosurgery orifspinalcord injuryissuspected) .

OR 4L .4?vF/t7&.t(7tff.,4# F:
Warfarin
'Ysoyrce;Synthetic .

*chem istrv.'Coum arin derivative .

*p harm acokinetics .
.

*A bsorption:absorbed orally .

wDistribution:highly boundtoplasmaproteins(99?4)-passesplacental
barrierand m ay cause teratogenicity .

*Fate:m et>bolized by I'IM E and very sm allam ounts are excreted in

breastmilk (* notsecretedinbreastmilk).
'Yp harm acodvnam ics:
-
M echanism o action:inhibitvitam in K epoxide reductase thus
irthibiting re tneration ofactive reduced vitam in K from vitam in IQ
-

epoxide-needed forcarboxylation ofprothrombin (faetor11),factorsVI1

1X , and X . ,
-
pharlnacologicalactions .
.

Indirectanticoagulantacting in vivo only, characterized by the follow ing:

A dvantaz:.î '
,.

l-Easy route of adm inistration .

z-lwongduration ofaction (4-7days).

bisadvantages:
l-Delayed onset(1-2 days):itdoesnotacton alreadyformedactive
(carboxylated)coagulation factorspresentiIablood butactby inhibitilpg
release of ''new ''active factors,so the action is delayed until
disappearance ofthe already form ed coagulation factors w hich m ay take
severaldays. '
z-Liableto severaldrug interactions(seelater).
3-contraindibated in pregnancy.
*controlofdose:
1-prothronlbin time (PT).
- - '
-
N orm al:12-15 seconds.
'
-
A fteroralanticoagulants:PT should be 2-2.5 tim esthenorm atvalue.
l-lnternationalNormalizedRatio (INR).
'itisaratio between PT ofthe
patient/PT ofcontrol.Itshould be 2-3 afteroralanticoagulation.
WhiteKnightLove

10
'It is more blessed to give than to receive.

*zjdverseelfects:
l-l-lem orrhage from any site is the m ostserieus advel-se effeet.

2-G utupsets' .anorexia,nausea, voimiting,and diarrhea.

3-A llergic reactions:skin rash .

4-Teratogenicity (abnormalbonedevelopment).
s-skin necrosisisrarebutseriotlstmay bedueto rapidelimination of
anticoagulantproteinsC and S beforecoagulation factorsareelim inated
leading to liability ofform ation ofthrom biin skin blood vessels, itis
preventedbyco-adminiitrationofheparin).
6-Druginteractions(seelater).
*Reversalofaction..
l-stop the drug.
z-v itam in K isthe specit'ic alntidote, e.g.vitam in K 1
3-Fresh blood transfusion .

*contraindications:
A sheparin ni
-Pregnancy .

*D rug r-Fc/cl-tzc/jt?zy-s.
.
'

A-pharm acokinetic interactions .

.

@A bsorption:cholestyram ine decreases absorption oforalanticoagulants .

*D istributi n:severaldrugs displace oralanticogulants from plasm a

proteinsasNSAIDS(aspil-in,phenylbutazone,indomethacin),
sulphonam ides,sulphonylureas, propranolol,verapam il,loop diureticsas
frusem ide,and clofbrate .

*M etabolism :
I-IM E inducersasphenobal-bitone,phenytoin, rifam picin,and tobacco
-

sm oking increase clearance of oralanticoagulants and m ay lead to

decreased PT and the patientis atrisk ofthrom bo-em bolism .

I-1M E inhibitors as cim etidine,erythrom ycin, ketoconazole,

-

claloram phenicol,and allopurinoldecrease clearance oforal

'
anticoagulants and m ay lead to excessive prolongation ofP-I-and
bleeding.
B -p harm acodvnam ic interactions.
.
*Drugsthatincrease the effectiveness oforalanticoanulants:
-

l-lnhibitiortofvitam in K synthesis by gutbacterialtlora:broad spectrum

antibiotics especially incom pletely absorbed'
.am picillin and tetracyclines.
z-lnhibition ofvitam in K absorption by liquid paraffin.
3-lnhibitionlofvitam inK activation asaspirin (largeand toxicdos
( es),and
cephalosporins.
These drugs as w ellas som e pathologicalconditions asliver distlases,
obstructivejqundice,andhypel-thyroidism (increasecatabolism ()f
coagulation factors)increasePT and subjectthepatienttobleeding.
WhiteKnightLove
 Freely you have received; freely give.

lD rugsthatdecrease the effectivelaessof oralanticoasqulants:

l-Excess vit'am in K (in greenvegetablesh
. -..
z-Estrogentöralcontraceptives)increasessyntl
aesisofcoagtllation
factorsl1,V I1,1X ,X , and illhibits antithrol-
nbin 111.
These drugs as w ellas som e pathologicalconditions ashypothyroidism
(decreasesturnoverofcoagulatiohfactors)andhereditaryresistanceto
oralanticoagulantsdecreasePT andspbjectthepatienttothrombo-
-
em bolism .,

F actors increasing P T F lc/o/a decreasing P T

(lncreaseactivi ofwararinl (Decreaseactivi c/ivtpr/t
-w-ïr?zl .
l-D rugsthatdisplace w arfàrin from 1-D rugs thatdecrease oralabsorption
plasm a proteins. ofw arfarin as cholestyram ine .

2-1-1M E inhibitors. Z-HI

M E inducers .

3-lwiquid paraffin. 3-Excess vitam in K .

4-B road spectrum antibiotics . 4-Estrogen.

s-Aspirin (larg'eand toxicdoses)and s-pathologicalconditionsas
cephalosporins. hypothyroidism and hereditary
6-Pathologidalconditions as liver resistance
.

diseases,obstructiveJaundice,and
hyperthyroidism .

UsesofAnticoagulants.
.
l-A nticoagulants are now used prim arily in prophylaxis ofD V T and
pulmonary embolism inhighriskpatients(slmok-el-s-obese-l-eculanbentas
postoperativepatients-laypel'litaiûlelriaand atherosclel-osis).
z-u nstable angina.
3-* Treatm entofpulm onary em bolism .
4-* Treatm entofacute m yocardialinfarction .

5-* Treatm entofcerebralthrom bosis

6-l-leparin isused in: A
*Dissenninatedintravascularcoagulation (L)1C).
eprevention ofblood clotting during blood transfusion and dialysis .

ll-lyperlipidem ia.
Choice ofAnticoagulants:
Stal'
tby co-adm inistration ofheparin and w arfariln for about4-5 daysthen
heparin is stopped and w arfarin is continued alone afterbeing sure of its
.

anticoagulantaction (PT shouldbe2-2.5timesitsnormalvalue).

.

R em enaberthatduring pregnancy heparin is used alone.

Ezklt/g'c/ct?z/1-anticoagulants:l-proteinsCandS. z-Antithrombin111.
,

3-1,
-ibl-inolysin.
WhiteKnightLove

12
'It is more blessed to give than to receive.

fff xpzj-lkLhl rJr

z'z4#F-z1-2-r-Ar
-

-
Source.. A nil-naio/l in . S Jnthetic.
' -

Chem istly: M ucopolysacchal'ide strolpgly

-
Coum arin derivative .
aeidic-Electronegative .

Pharlnacokinetics: -'N otabsorbed orally given only

-
IV or SC butnever IM
-D oesnotpassplacentalban-ier
A bsorbed orally-highly bound to
. plasm a proteins-pass placental
ban-ier m etabolized by the liver
-

and notexcreted in breastm ilk . and m inim ally excreted in breast

-
lkapidly cleared by RE S and m ilk .

m etabolized by the liver.

..

Pharm acodynam ics:

--ah
#tcc>trknz'
xF3i. -A ctivates antithrom bin 11land lnhibit
svitam in K epoxide
inhibits active factorX , throm bin reductase thus inhibiting
and otherfactors. carboxylation ofprothrom bi
n
and factors V l1,1X , and X .
-zqctions: l-A nticoagulant130th in vivo and A nti
coagulantin vivo only-
in vitro-D irect-R apid onsetand Indirect slow onsetand long
-

shol-tduration. dtlration,
z-Lipem ia clearing factor.
3-slightV .D .
4-lnhibits lateleta ere ation .
- -
Controlc?/'#tn.
îc.
' 1-aP'
1-T. 1-PT .

z-coagulation til-
ne. 2-1N R .

A Jverse effects: l-l-lemorrhage. 1-Llemorrhage .

z-l-lypersensitivity. z-l-lypersensitivity.
3-o steoporosis. 3-G utklpsets .

4-A lopecia. 4-Teratogenic and affects

s-Tlnl-olnntnûltzytolaelnia and stlckling babies .

paradoxicalthrolmbosis. s-sltin necrosis .

Reversa/ofaction..
6-l-lyperkalem ia.
l-stopthedrug. l-stop t14edrug. -
z-protam ine sulphate IV z-v itam in K IV
(specificantidote). (speei'
ficantidote).
3-lR1-esh blood transfusion. I3-l7resh blood transftlsion. -
WhiteKnightLove
 Freely you have received; freely give.

V-Treatm entofzqnem ias

Treatm entq/-/-lç/zcjczkcrAnem ias

l-Treatm entoflron Dehciency Wz?cpçjtz.

. '
AD ietary iron is better absorbed from the dtlodenum in the form of
fen-ous iron.
AAbsorption isenhanced by gastricH CIand vitam in C and reduced by
phytate and phosphate.
#lron deficiency anem ia occurs due to dietary defsciency, decreased
absorption,and chronic blood loss.

A -o l-aliron pl-eparations:
*Exal-
nples:F errousgluconate, Fcrrtnî/:hlmarate,and iron choline
citratewhich istheleastirritant(Fen-oussulphateisnotused asitisvery
in-itanton G1T).
*A dverse effects:
l-G utupset:epigastric pain, colics,diarrhea orconstipation
z-A cute iron toxicity.
.m anifestatiùns include nausea, vom iting,severe
colics,hem atem esis,and black orbloody diarrhea. Itm ay cause
hypotension,'collapse,and finally com a.
.

*Treatm entofacute iron toxicity:

-
stom ach w ash by N aH CO 3.
-
lron chelating agentasDesfertioxamine given orally orparenterally .

Symptomltictreatmentas1v 1l
'uids.
B -parenteraliron preparations' .

*Exam ples:
-
lron dextralu IV or1M .
-
lron sorbl'tolcitric tacfc/com plex:1'
&1tonly .

*Toxicity ofparenteraliron:
-
Localeffects:pain and skin discoloration atthesiteofinjection.
'
-
systemiceffects'
.headache-malaise-muscleandjointpain-
bronchospasm -hem olysis-fainting-hypotension-elncephalopathy .

*Treatm en toftoxicity:
-----

-
lron chelating agentasD es/krr/tlxt
- pr/c/ntagiven parenterally.
-
sym ptom atic treatm entas IV fluids.
WhiteKnightLove
'It is more blessed to give than to receive.

2-Treatm entofpernicious-/lncpc/k .
'

APernz
1cz
lous anem ia is com m onlt
-'due to r1m
V1Ux4
Y*
-
xrx.
1G *e
1.
'
z
/g1U/
Q ,
vxx1gs
43* *gyg*
-gy(gy
y yg X
ygG(.
gy*
requiredforabsorption ofvitaminB1a(extrinsicfactor) .

AD rugsthatdecrease absop tion ofB I2and m ay cause pernicious anem ia

include:M etform in,N eom ycin, apd Para-am ino salics'lic acid .

AM anifestations ofperniciousanem ia include'm acrocytic anem ia + CN S

.

disturbances(peripheralneuritisandsubacutecombineddegeneration of
thespinalcfrd)+ GI'Fmanifestations(glossitis,achlorhydria, gastritis
and diarrhea).
A'
Freatm ent:
l-cyanocobalamin (lmg.IM maybeused forlife)
.
.
$'
z-l-lydroxocobalamin (alsoused in treatmentofcyanidepoisoning=
cyanidechelâting agent).
N .B .:
1-N evertreatpel-nicious anem ia by folic acid alone as itw illcorrect
blood picture butaggravates CN S and G 1T m anifestations .
z-N eom ycin,m etfol-m in, and PA S reduce oralabsorption ofB Ia .

3-Treatm entofFolic Acid .

Dty//
. -c/c/kcv A nem ia .

(M egaloblasticAnemial:
#causes:
-
pregnancy:increasesrequirem ents for folic acid .
-
DecreasesGIT absol-ption
'
.

-
l7ru(z'
-
,
5... t
l
l-D ihydrofolate reduetase inhibitors'Trim ethopriln Proyuanil
.

P
- y1'
> / i
z-A ntiepileptic drugs w ith potentl E induction'Phenvtoin .

Carbam azepine Barbiturates .

q-hfethotrexate(antimetaboliteanticancerdrug).
A-f-reatnnent:Folinicacid (activetetrahytll-ofolicacid 1etlcovol'inl. WhiteKnightLove
 Freely you have received; freely give.

4
.

B lood D isorder Causes Fz-t?t7//?:cr2/

l

G ranulocylopenia l-A nti-cancerdrugs . l-stop the drug.

(Agranulocytosisl: z-Anti-fungaldrugsasAmphotericin z-Fresh blood transfusion.
.

3-Anti-viraldrugs as Zidovudine 3-B road spectrum

.

4-A nti-thyroid drugs:Thioam ides as

. penicillins .

m ethim azole and-carbim azole . 4-A nabolic steroids and

s-A ntiainflam m atory drugs'Pyrazolone glucocol-ticoids
. .

derivatives(phenylbutazone),Indole s-l-lematopoeiticgrowth
derivatives(indom ethacin),gold salts factorsaserythropoietin
(used in rheumatoidal-thritis) . granulocyte colony ,
6-Anti-bacterialdrugs: stimulating factor(G-
chloram phenicoland sulphonam ides .
CSF),orgranulocyte/
7-A nti-epileptic drtlgs:carbam azepine . m acrophage colony
stimulatingfactor(GM -
A CSF).
plasticAnemia: lonicinhibitorsasperchlorate(were 1-stop thedrug ; .

used asantithyroiddrugs)+ mostofthe z-Freslnbloodtransfusion ': .

drugs causing granulocytopenia . 3-Anabolic steroids and :
glucocolrticoids. t
4-l-lem atopoeitic grow th
factors as erythropoietin.
5-B Ja,folic acid,and
vitam in C.
l

M etlaem oglobinem ia:1t l-prim aqulne. Redtlcing.agentsas .

z-sulphonamides. vitamin C (ascorbicacid) '
3-phenacetin. orm etlnylene blue.
4-Nitrites(morethan nitrates).
)
l
' .-- .
w- s - )
lemolyticAnemia(in 1-Aspil-in. 1-Avt7lddrugsllAdtlcing
def'iciency ofG-6-PD): z-sulphonal-nides. hel-
nolysis.
3-prilraquine. z-Fresh blood transftlsion
4-phenacetin. Orpacked 1tBC S..

s-lsoniazid.
j
WhiteKnightLove

16
'It is more blessed to give than to receive.

V1- Frctz//zzc/z
?/o' cr//'p/'lcp.
?/'tz5'
STA 77.
V N,: FIB l?A 7-5,:
. B ile acid xs.tdt
yr/r
.
y-y/?-t
:
?Fcs'
(bileacid-binding
rt?.
çpr,
sr
-) - - -
Examples.
. Sitnvastàtin- Clofibl'ate-l--'enof'ibrate- Cholestyram îne -
1
Lovastatin-pravaxtatin- Gem fibrozil 1
Atorval atin; -
.
Colestipol !
Actions: lrtcholesterol l-t-
l-riglycerides l-Bindto (sequester)
synthesisby inhibition IIyJVLDL synthesis bilesaltsin the
ofI'
IM G Co-A andoutputfrom the intestineinhibiting 1
1-eductase. liver(bytlipolysisin theirentero-hepatic 1
Z-tI-DL inblood adiposetisstlesand recycle
e compensatory 'tin tFFA supptytothe N compensatory 'tin
hepaticLDL liver)and IVLDL hepaticLDL ;
receptors- âuptakeof clearance from plasma receptorse luptalte
cholesterolby (lactivity of ofcholesterolby !
hepatocytes. lipoproteinlipase). hepatocytesto l
3-1'11DL. Z-tLDL. synthesizebilesalts .

4-tTriglycerides. 3-II-IDL (most Z-tLDL.

effective,especially 3-N o effecton LID L
em fibrozil . ortricrlycerides.
Uses: A lltypes of l-llrpel-tl-iglyceridelnia- H ypercholestel-olem ia
hyperlipidemias(the M ixed hyperlipidemia. inpatientsintolerant
m osteffective drugs). to otherdru s.
'
AdversccJ/-
t?c/.v.
' (
1t
-
ra
1-)iverelzyl
-nes
,
1-'
t1iverenzynlesand 1-constipationand j
nsaminases)and ' may behepatotoxic. distension (maybe I
maybehepatotoxic. z-lcreatinekinase usedintreatmentof l
z-lcreatinekinase (CK)andmaycause refractol-y diarrhea, i
I
(
PK)andmaycause my
myopathy.
opathy.
3-Gt1tupset.
seeG1T
phannacology).
1
1
3-G t1ttlpset. 4-G al1stones z-l3ecl-ease î
4-l-
leadache. (cholelithiasis)and absorptionofmost j
s-Teratogenic. choleiystitis. drugsasdigitalis, !
6-D isplace oral s-D isplace oral w arfarin,and fat-
anticoagulants from anticoagulants and soluble vitam ins.
Plasm a proteins. sulphonylureas from
'
plasm a proteins. .

6-/tllergy and blood

(yscrasiasis.
C ontra- l-pregnancy and l-pregnancy -lactation.
'
Jndk ations.
. lad ation. 2-LiVer diseases.
I
. z-Livel-diseases. 3-G a1lbladder diseases - - - j
WhiteKnightLove
 Freely you have received; freely give.

O ther W /c///c'
kw t.
y/-//p/ti/cv /c D rl/gx.'
. .

Niacin (nicotinicacidl:asfibrates(JLDL andVLDL synthejisbythe

.
liverand ylipoprotein lipase--ytcholesterolandtriglycerides) .

A dverse effects:
1-/'
/1/.
9/?7'/Jg dtle to PG release, thisisprevented by aspirin adm inistration
before niacin.
2-GlT disturbances. .

3-H yperuricem ia and hyperglycem ia .

4-Elevation of serum trànsam inases .

E 1l
zetim ibe:decreases absorption ofdietary and biliary cholesterol .

WhiteKnightLove

18