Drugs used to treat

Diseases of BLOOD

617
 BlueprintTi\l Pharmacology
I

618

Anti-thrombotic dru s
Hemostasis: Hemostasis is the process of forming clots in the walls of damaged blood vessels and preventing
blood loss while maintaining blood in a fluid state within the vascular system .
(Ref Ganong-24th)
Steps of hemostasis: When a small blood vessel is ruptured or severed, hemostas is is achieved by the followi ng
steps:
I. Vascular spasm (or vasoconstriction)
2. Formation of platelet plug
3. Blood coagulation
4. Fibrous organization or dissolution of blood clot.

Formation of platelet plug:

Platelet adhesion: When the endothelium is injured, platelets adhere to the subendothel ial co llagen by von
Willebrand factor (vWF). ·----

Platelet activation: After adhesion, platelets undergo morphol9gic changes and become activated and then
release granules containing adenosine diphosphate (ADP), hromboxane A2 serotonin, platelet-activation
factor (P AF), and thrombin. ?G
l
Platelet aggregation: ADP, thromboxane A2, serotonin, and PAF bind to the resting platelets circulating
nearby and activate them. Intrace llular Ca-+ mcreases in these acti vated platelets.
l
Increased cytosolic Ca2+ leads to
~ Release of platelet granu les containing ADP and serotonin that activate other platelets.
/ Activation of thromboxane A2 synthesis.
/4Activation of the glycoprotein (GP) IIb/IIIa receptors.
l
Activated GP fib/IIIa receptor binds with fib rinogen

One fibrinogen molecule binds to GP llb/Illa receptors 0~1 two se~_!ate platelets, resulting in platelet-cross-
link ing and platelet aggregation. ( R,n.~(T"{"-- oQ.._ r~~~\~ p\'-0
:} (Ref Lippincolf 's-6th)
Importance of platelet plug for closing vascular holes: If the hole in the vessel is small, the platel et plug by
itself can stop blood loss, but if there is a large hole, a blood clot in add ition to the plate let plug is required to stop
the bleeding.
 6 I IJ Dru gs used lo trea t th e diseases of Blood

Woll delOCI

l
Fibrin

~ Throm• , - - -- Prolh rombln

A Fibrinogen

Figure: Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and the role of
platelets and clotting factors . Platelet membrane receptors include the glycoprotein (GP) Ia receptor. binding to
collagen (CJ,· GP lb receptor binding von Willebrandfactor (vWF), and GP J!b/I!!a, which binds }lbrinogen and
other macromolecules. Aggregating substances released from the degranulating platelet include A DP,
thromboxane A 2 (IXAi), and serotonin (5-HT).
(Ref Katzung-13th)
Anti-thrombotic drugs include-
• Anti-platelet drugs
• Anti-coagulant drugs

ntiplatelet dru s
Q. List e anti-platelet drugs. (DU-l 7M, 16J, I 1Ju,09J,08Ju; CU- I6Ju,08Ju ; RU-I 3J, I 0J,05M ; SU-09/06J )
egorize anti-platelet drugs. (CU - l 4J)

ssification of anti-platelet drugs:

I. landin s nthes is
2. ADP receptor inhibitors : In hib ition of ADP induced plate let aggregation.

3. Inhibitor of glycoprotein lib/Illa receptors on platelets (intrave nous use Abcixi mab
only) • Epti fi batide
• Tiro fiban
4. latelet-directed dru 1 s
•
• Inhibitor of ad enosine u take and cGMJ> Jhos Jhodiesterase Dipyridarnole
(Ref Katz1111g- l 3th)

~ 3 cl inically useful antiplatclet drugs. (CU-07 Ju)

3 clinically useful anti-platelet drugs:

I . Low dose as pir in (75 - l 50 mg per cl ay)
 Blueprint TI\I· Pharmacology 620
2. Clopidogrel
3. Abciximab

How does low dose aspirin. act as anti-platelet"action? (DU- l 7M,09J)

Explain ie mechanism of antiplatelet action of low dose aspirin . (DU-I I Ju,0807/J;RU-05M,SU-09J,08J)
Justif the use oflow dose aspirin in the management of thromboembolic diseases. (CU-08J,SU-03S)
°' does aspirin produce antiplatelet effect? (DU-16J,07J; RU-05M,04M ; SU-091,0JS/J)
G · e explanation of anti-platelet effect low dose aspirin. (RU-1 OJ)
xplain the role of low dose aspirin in heart clisease/IHD. (SU-1 JJ, 12Ju)
S4ort nqte: Lo-vy (Jose aspirjn. CQ1J.-n.1t,j1)) ..
Ans. ·
Mechanism of antiplatelet action of low dose aspirin : Low dose aspirin inhibits platelet aggregation by
inhibiting thromboxane A 2 formation.

Aspirin (acetylsalicylic acid)

l
Acetylates and thus inactivates cyclooxygenase enzyme (COX) irreversibfv
l
The platelets are unable to synthesize new enzyme
l
COX activity is lost for the platelet life time (8 - 10 days)
l
Prevention of formation of both thromboxane A 2 and prostacyclin.
l
Thromboxane A 2 causes platelet aggregation but prostacyclin inhibi ts platelet aggregation. Low dose aspirin
(75 to 150 mg/day by mouth) will abolish synthes is of thromboxane A 2 without significant impairment of
prostacyclin formation .
l
Thus low dose aspirin Inhibits platelet aggregation.

By preventing platelet aggregation, low dose aspirin prevents formati on of thromb us . This is how aspirin
prevents thromboembolic diseases, eg, myocardial infarction , stroke, deep ve in th rombos is, etc.
(Rej: B ennett & Brown-11th)

lain the mechanism of action of clopidogrel as anti platelet drug. (C U- l 6Ju , SU - I 7M ,06/05J)

chanism of action of Clopidogrel / Ticlopidine: Clop idogre l and t ic lopid in e red uce plate let aggregat ion by
inhibiting the ADP pathway of platel ets.

Clopidogrel I Ticlopidine
l
Irreversi bly blocks the ADP receptor on pl.atel et mem bra ne
l
No binding of ADP wi th ADP receptor
l
No activation of the g lycoprotein lib/ Illa receptors required for plate lets to bind to fibrinoge n and to each
other
l
No plate let aggregation (antiplatelet effect).

By preventing platelet aggregation, c lopidogrel prevents formatio n of thrombus . This is how clopidogrel
prevents thromboembolic diseases, eg, Ml, stroke, deep ve in thrombo sis, etc.
(R ef Katzung- I 3th + Lippincott 's-6l h)
 Drugs used to treat ti1c u- 1· scases- of Blood
1
621
Q. W 61110 you mcnn by low dosl' aspirin'! (CU-1SJu)
Q~'kfly discuss ahout low dosl' aspirin with clinical importance. (SU- I JJu )
1ns. I ·b·
Low dosl' nspirin : A dnil y lost' or 75 -150 mg oraspirin is ca lkd low dos1: asp irin . I ,ow dose a'i pi rin in 1 1 its
platelet aggregat ion by inhibitin g thrc m oxanc A2 to rm ati on.

Clinic.11 import ance: Write i11dicotio11sji·o111 below.

Nici! to kn ow
Reference of low dose aspirin
• 75 - 150 mg pa day (Ref- Bennell & Brown-JOtl' edition)
• 75 - I 50 mg! day (Ref Davidson 's-2 }"' edition)

Q. Mention the indications of low dose aspirin with justification. (DU -08J , RU - l 4J, 12J u)
Q. Name 4 indications of aspirin for anti-platelet effect. (RU- l OJ)
Ans.
Indications of low dose aspirin / clopidogrel:
J;Myocardia l infa rction (M I)
-~ Unstable angina (UA)
/-, lschemic stroke
;{ Trans ient ischemic attacks (TIA)
,¥. Peri pheral vascular di seases (PVD)
·vFollowing coronary artery angiopl asty & bypass grafting.
7,_ Patient with prosthetic valve.
~Deep vein throm bosis.
1 Atria l fi brillation.

Clopidogrel is used either alone or in combination with aspirin. It is given to patients who cannot tolerate aspirin
such as patients with peptic ulcer disease (PUD) with active bl eeding, severe bronchial asthma; because aspirin
aggravates PUD and asthma.

Q. Rationalize the use of antiplatelet drugs in a patient with cerebro-vascular accident. (RU -13J)
Ans.
Antiplate let drugs prevent platelet aggregation and thus prevent fo rmation of thrombus. If a patient of cerebra-
vascular accident (ischemic stroke) receives anti platelet dru gs, these drugs prevent further attack of cerebra-
vascular accident.

Q. Mention the adverse effects of low dose aspirin? (DU-11 Ju,SU-06M)

Ans.
Adverse effects of aspi rin :
/.: Gastric irritation
f Gastric hemorrhage
1, Gastric perforation (drug induced peptic ulcer perforation)
f. Precipitation of asthma.

Q. Mention the contraindications of aspirin?

An s.
Cont91indications of aspirin:
X. Peptic ulcer disease/ active bleedin g PUD
.,,2:. Coagu lation disorder
A. Asth ma
y Chro nic obstructi ve pulmonary di sease (COPD)
Y. Pregnancy ( Isi trimester).
Pharmacology-80
-Q.Bl~u!:.q~H~
t !!
. ·i~n.!.t'_'_'.!.P!h~11_'r:.:,
l\kulio n (h l'
. m:,::11~l'_::o.l,:,:1
· _ _ _ _ _ __:<
lg_:;:~_ 1~2~2-:-------------------
1<h l' rsc d'fr l't s of tldopi di1ll' . (t 'IJ- 1(,.111)
---.....
Ans .
A1h l rsl' d'frcts of tido pill in l·:
l . N:1us~·:1
I)> sprps i:1
J. l i:mh~::1
-L l k nll,rrh:11.:c
5. Ti\·l\,pidine ( !lltsl;s lik thrcatcn in, blood abnormalitic · such a · ncutropcnia, agran~l o~ytos i ·, thrombotic
tlm)mbocylOp 'n ic purpura ('17'P) & aplastic anemia . For these adverse effects ll I re ·crvcd for the
patients who are not uitable for a pirin / clopidogrel therapy.
(Ref Lippincoll 's-6th; Katzung- l ]thJ

Q. Mention the adverse effects of clo piclogrel.

Ans.
dverse effects of clopidogrel
Thrombotic thrornbocytopenic purpura
2. Clopidogrel is rarely associated with neutropenia.

Viva Q. Which one is preferred- ticlopidine or clopidogrel?

Ans.
Because of its superior side effect profile and dosing requirements, clopidogre/ is preferred over tic/opidine. The
antithrombotic effects o} clop1dogrel are dose-dependent; within 5 hours after an oral loadTng dose of 300 mg,
0% of platelet activity will be inhibited. The maintenance dose of clopidogrel is 75 mgld, which achieves
maximum platelet inhibition. The duration of the antiplatelet effect is 7-10 days.
(Ref Katzung-l 3thJ

Q. Compare the mechanism of antip!atelet action ofaspirin & clopidogrel. (DU-08Ju)

Q. Compare the mechanism ·or action.& adverse effects of aspirin & clopidogrel when used as antiplatele1
drug. (CU-08Ju) . .· ,
Q. Write own differenc~s between aspiri~ an~ clopidogrel. (SU-03M/S/J; RU-OSM)
Ans/
D' ences between Aspirin & Clopiclogrel:

Inhibits thrornboxane A2 Block ADP receptor on

s nthesis latelet membrane
2. Anti-inflammatory effect Present Absent
3. Anti- Jyretic effect Present Absent
4. Effectiveness Less effective More effective
5. Cost Ex ensive
6. Yes
7. Yes No
8. No Yes

Q. Short note: Aspirin & clopidogrel as antiplatelet drugs. (RU- 14J u)

Q. hort note: Clopidogrel. (RU-16J)
Ans. Write in brieffrom above.

Viva Q. Which anti-platelet drug will you prefer for a patient of Ml who ltas history of broncltial astltma?
Ans.
C/opidogrel.
 . scs of Blood
623 Drugs used to treat the d isea

,4, a. tk·Ei4i, P., az; ;; rm

Blood coagulation :

TFPI

Thrombomodulln
@)+TF Vila -TF Endothelial cells

Xia Protein C~ct

j1xa I
(Villa)

[fil

D Inhibited by heparin
®
0 Inhibited by oral
anticoagulant drugs
Prothrombin II ~Thrombln

C) Down-regulated
by protein Cact
(\
la
Fibrinogen Fibrin clot

Fig. A model of blood coagulation. With tissue factor (TF),factor VII forms an activated complex (VIIa-TF) that
catalyzes the activation offactor IX to factor IXa. Activated factor XIa also catalyzes this reaction. Tissue factor
pathway inhibitor (TFPI) inhibits the catalytic action of the VIIa-TF complex. The cascade proceeds as shown,
resulting ultimately in the conversion offibrinogen to fibrin, an essential component of a functiona l clot. The two
major anticoagulant drugs, heparin and warfarin (an oral anticoagulant), have very different actions. Heparin,
acting in the blood, directly activates anticlotting fa ctors, specifically antithrombin, which inactivates the factors
enclosed in rectangles. Warfcirin, acting in the liver, inhibits the synthesis of the factors enclosed in circles.
Proteins C and S exert anticlotting effects by inactivating activated factors Va and VIJia.
(Ref Katzung-l 3th)

Q. How fluidity of blood is maintained in vivo? (CU-16Ju)

ry-- Ans.
°'-. Fluidity of blood is maintained in vivo by preventin g intravascular coagulation by the fo llowing factors-
1. Endothelial surface factor: Pro bably the most imp01tant factors for preventing clotting in the norm al vesse l
are-
/4 Smoothness of the endothelial surface prevents contact activation of the intrinsic pathway.
p. Glycocalyx layer on the endothelial surface repels the platelets & clotting factors and thereby prevents
activation of clottin g.
/4 Thrombomodulin, a thrombin-binding protein, is produced by endothelial cells. It acts by two ways-
• It binds with thrombin ~ tthrombin ~ tclotting.
• Thrombomodulin-thrombin complex activates protein C.

2. Speed of blood flow: This prevents intra vascul ar clotting of blood.

3. Presence of natural anticoagulants:
a. Heparin: Secreted by basophil & mast cell. It acts as a co-factor fo r antithrom bin Ill.
b. Antithrombin III: It comb ines with the thrombin and thus, blocks the effect of thromb in on the
fibrinogen . The complex of antithrombin lll & hepar in inhibits the activated factors IX, X, XI and XII.
 Ti\l
Blueprint ' Pharmacology 624
c. r1hrin: It has antithrombin action. Whe n a c lot is fo rming, about 85 - 90 % o f thrombin bccornes
absorbed to th e fibrin fibers as they deve lop. This prevents the s pread of thrombin into the re maining
blood and, th e refore, prevents excess ive s pread of th e clot.
cl. Protein C: Ac ti va ted protein C (APC), along with its cofactor prote in S, inactivates fac tors V and YIIJ
and in ac tivat es an inhibit o r of tissue plas minogen ac tivato r, increasi ng th e formation of pla sm in .
e. Protein S: Acts as cofactor for prote in C.
f. llepari11 sulfate

g. a 2 macroglobuli11 : Binds some clotting factors & prevents their action.

4. Plasmin (Fibrinolysin) : This enzy me lyses fibrin and fibrinogen, with the produ ction of fibrin ogen
de,5 rad atio n products (FDP) that inhibit thrombin.
(Ref Guyton-I 3th; Ganong -25th; Conc ise-6'hl72, 73)

'Q. f..: lassify 'a·o.ticoa·g ula1i.ts . .(RU~06S, SU..'. J3J;08~,iCQ::"12J;O$>Jti) .

Q · tion the different anticoagulants. '(DU~16Ju)'4J) : ·
umerate in-vivo anticoagulants: (DU-05S) · .
ame the orally acting anticoagulants: (CU--;06S)'
1----£. ame the lo'Y,.!PQl~c~ta_r.weig_h ( heP,_arili (]LMW),p~~pa_r ~tjons. (DU-1 0/_08/ Q7J; CU-06l'yf, RU-12J)
_/ ·:ns .
' Anticoagulant drugs: Anticoagulants are the drugs which are used to prevent unwanted coagul atio n.
A. Anticoagulants acting in vitro: r~ ~)
I. Heparin
2. Ca chelating agents
• 3.8% Na citrate
• Na+-oxalate

B. Anticoagulants acting in vivo: (__~-2)

1. Parenteral anticoagulant drue:s ./
• Indirect thrombin inhibitors 1. Unfractionated heparin (UFH) / standard hepari n /
regu lar heparin
2:. Low-molec ul ar weig ht (LMW) hepa rin I
fract ionated heparin / irreg ular hepari n:
, .,,.. Enoxaparin
,•' /- Da Itepann.
-·
• T inzapa rin
3. Synthetic pentasaccharide
• Fond aparinux
• Parenteral direct thrombin
inhibitors ,,y Hiru din
/
Lepi rudi n
• B ivali rudin
• A rgatro ban
2. Oral anticoagulant drue:s
• Coumarin anticoagulants .• Warfarin
• Dicum a rol
• Oral direct th ro mbin inhibi tors • X ime lagatran (1111ithdrawn fro m th<' market becaus e of
hepatic toxicity)
• Dabi gatran

C. Anticoagulants acting in vivo & vitro : He par in .

 625 Drugs used to treat the dis eases of Blood

Heparin
Heparin
. is_ a hetcro 0
1 1: Ll 1· .ll If'atcc I mu co polysacc harniL:s.
_ ::--cneous' 111 1··'v t11·, · It bi·nds to cnd otI1e 11a - 1-1·dcc_
· I cc II su ·s '·-111 d ·1
c
vanety ol plasma pro tein s.

Viva Q. Why heparin is not admini.,·tered orally?

Ans.
Heparin is not administered orally, because- ~ o , C'•-
1. Di~ on of heparin b am lase as it is 11111cupulysacc:haricle.
I \~ ,~ \.._,. .----\ _ ,. rr....:. ' ' ~
2. Le s a surpt,on due to negative charge. &,-, 'f "\
. ..
Viva Q. Wiry lr eparm 1s not administered intramuscularly ?
L', C, f -y-\\ ,.., .\ I ( -,. .J.µ ?
.,..
.,.f.__
Q '-'..
1~ )
=. •. -r ...
A,,~ -1- '
Heparin is not administered intramuscularly because there will be /r ematoma f ormation at the site of injecdon.
1:\1 inj~ction of heparin - Bleeding - ! Coagulation due to act1611 of heparin - More bleeding -, Hematomu
fo rmat10 11.

Q. What do you mean by LMW hepai·in? (RU-071,06S)

Q. N~me the low molecular weight heparin (LMWH).,(RU-13Ju)
Q. Briefl iscuss about low molecular weight heparin with clinical importance. (SU- l3J u)
Q. S o note: Low molecularweigh( heparin. (DU-13J, 12J,SU- 15Ju,1 2.l u)
A s.
-,. ,_ -~ --=='"'~.r weight heparin (LMWH): The LMWHs are heterogen eous compounds (one-th ird th e size of
unfractionated hepari n) produced by the chemical or enzymatic depolymerization of unfract1onated heparin.
Because they are free of some of the drawbacRs associated wi th the polymer, they are replac in g the use of heparin
in many clinical situations.
(Ref Lippinco!! 's-6th)
Q. Explain t~h an itoagulant mechanism of heparin. (DU-13Ju,1 Uu, CU-13Ju,07J; RU-07J, SU-07S)
Q. How does I H acts? (SU-09J)
Q. Exp!?i'n) e anticoagulant action of enoxaparin. (SU-l 7M, 11 Ju)
Q. Shory<ote: Enoxaparin. (SU-14Ju)
Ans:Z.- · -
· Ahticoagulant mechan ism of heparin : Its biologic activ ity is dependent upon the endogenous ant icoagu lant
antithrombin III (AT-III).

Acti ve heparin binds tightly wi th AT-III

!
Conformational change in AT- lll mo lecul e
!
More rapid interaction of AT-III with the seri ne proteases (activated clottin g factors Ila, IXa, Xa).
t
Formation of AT-III-Serin e protease complex.
!
Heparin functions as a cofactor fo r the ·AT- Ill -Seri ne protease comp lex' react ion wit hout being co1n 1med.
It actually potentiates the action of AT-Ill by 1000 times.
!
Inactivation of serine proteases (Ila, IXa, Xa) by the AT-I II.

• High-molecular-wei ght fractions of heparin with high affi nity fo r antithro mb in ma rked ly inhibit bl ood
coagu lat ion by inh ibiti ng all three factors, especi all y thro mbin (Ila) and fac tor / a.
• In contrast, LMW heparin inhibit factor Xa but have less effect on thro mbin .
-- (Ref Kat::ung-13th)
 Blueprint n, Pharmacology 626
~!1!!,!!!.!__!..!!,!!..!!!~~----~:-:-:----------------
J'ji, a Q. H l,y LMW Heparin inhibits 011~) ' Xa hy AT-Ill?
. Ins.
7iJ inhibit jhctors other th<III factor Xa, 2: 18 1110110.rnccha ride units are r equired But LM~ h e1:~rin has only J5
111011u.wcclwrid11. 1111i1s. Sv. J,/1/1 /1 heparin produces w1 a nticoagulant e/ject m ain ly throug h tnh1ht1wn vj Xa hy AT..
Ill.
(R e/ Goochnan u ilman-1 2 11, edition)

Q. i'\-tent.ion fht' indications of heparin . (DU-07 J,04S , SU- l 5J, U -021, RU -04M )
Q. l\'fo 1fio11 the therapeutic/clinical uses of hepa ri n. (CU- 1JJu; ' SU- 10)
Q. Mentio n fhe important indications of LMW heparfo . (DU-07J, R U-13 .lu, l 2J)
Q. 1ention the clini~al uses of ~noxaparin. (.QU-l 6Ju)
:\11s .
Indications / clinica l uses of Heparin/ LMW heparin/ Enoxaparin :
I . Acute Ml
2. Unstable angina ,, \ C C
3. Dee p vein thrombosis (DVT)
, (l.;.;f°r-:;_ <., ~ ~---y- /
4. Pulm o nary embolism
5. Angiogra m
6. Prophy lax is of deep vei n thrombosis (DVT) & pulmonary embolism in high risk patie nt unde rgo in g
surgery I stroke or other imm obilized patients
7. To maintain the patency of cannula & shunts in dialysis patients & in ext ra-corporal circu lation.
8 . Di ssem in ated intravascular coagul ation (DIC)
9. Cerebral infarction
10. Th o racic s urgery
(Ref Lippincott 's-6th)

Q )Vhat are the adverse effects of he parin ? (DU-I !Ju, CU-02J, RU -04M)
~ S.
J averse effects of heparin:
I . Hemorrhage.
2. Hypersensitivity reacti ons (chills, fever, urticari a or anaphy lactic shock)
3 . Thrombosis (due to reduct ion of antithrombin-III).
4. T hrom bocytopenia.
5. Osteoporosis leading to patho log ical fracture.
6. 1/ansient a Jopec ia.

Q. ~/ntion the contraindications of heparin. (SU -151)

Aris /
C ~ traindications of heparin:
I . Hypersens iti vity reaction
2. Bleeding disorders: Hemophilia, thrombocyto penia, purpura .
3. Preexisting hemorrhagic state: Chronic liver di sease (CL O), hepatic failure, rena l fa ilu re.
4 . Active bleeding peptic ulcer disease.
5. Recent cerebral hemorrh age / intracranial hemorrhage.
6 . Uncontro ll ed hyperten s ion
7 . Subacute bacterial endocarditis
8. Active tuberculos is
9 . T hreatened aborti o n
10. Large viscera l carci noma
11 . Recent surge ri es es pecially to eye or CNS .
12 . Lumbar puncture or regiona l a nesthetic b lock.
13. Heparin sho uld be used in preg nant worn n only w hen c learly indi ca ted.
(Ref Kalzung- l 3th)
 ("' i'..,...J
r o>~ ~ ~~
12> t ei& ·Pl0--o ~ -
1

--,,~
:P>f' P:i r_ ,'c:J ~c., C, "-1\
G " ~~ ~ ~ ~~ 0 \ ~ · \_\ Qf v-; · · 0 f Blood
627 Drugs used to treat the chseascs
,

.+ /,\.
1
Of
~
c
treatment with heparin is /11()/litored? ·l)\::.. \-
,_...-v-,__,._,~
; ~
p
~ r~ 7 (._ -~ C

Monitoring heparin therapy: ( ...:;::,.--,-. · . · ,..,.._s ~ '\...--r- ~ -.5. CL.(~\

1· Control 0f srandard heparin therapy is by the activated partial thromhoplastin timp(APTT), th e optimum
th erapeutic range being 1.5-2.5 times the control (which is preferably the patient's own pretreatment
APIT).
2. ~ n alternative method is lo measure the plasma concentration of heparin using an anti-Xa assay aiming
jar a therapeutic concentration of 0.1-1.0 Ulm/.
(Ref Bennett & Brown-! I th)

Monitoring LMW heparin therapy: Therapeutic doses of LMW heparin do not prolong the APTT and, h~ving
predictable pharmacokinetics, they can be administere usmg a O yweig t a uusled algorithn1 w//hout
laborato,y monitoring. If necessary an anti-Xa assay can be used to measure the heparin level.
(Ref Benneti & Brown- ! l th)

Q. Mention the advantages of' ~Mw,' liepafin therapy over CO~':_e·ntional 7 unfr~ctionated /standard
h~pari~? (DU- _10/Q8/07J, Cp -07):,0.6Ni!, Rtfll l2J,l'bJu,07J,06S, SU-1$},JOJu)
Q. Mention the advantages of~.nox~parin over·· unfractionate'd heparin'! (DU- 16Ju, RU-16Ju,14Ju)
:Q, What ar the advantages & i:li~advantages of reguiar hepari~ c_ompared to LMWH in the management
oft o boembolic disorder? (CU-13J,09~ · .,·
Q:_W. are th.e ad,vanj ag~s ~ disadvant~g~ o_f Lfy!)VJ ep~_I if!. as, a!!.!!f.oagula1't? (CU-05M).

tages of LMW heparin over unfractionatecl heparin (UFH) :

Better subcutaneous bioavai lab ility (70-90 %) compared to UF H (20-30 %): Variability in response is
minimized.
2. Longer & more cons istent monoexponential half life: Since APTT is not prol onged, laboratory
monitoring of LMW heparin therapy is not required. Dose is calculated on body wei ght basis.
3. Small effect on APTT & whole blood clotting ti me.
4. Thrombocytopenia is less frequent
5. A foWerhTci-ctence of hemorrhagic complications compared to UFJ-I.
6. More convenient to use.
7. Less frequent dosing (once or twice a day)
8. Suitab lefor ou door patient.
9. Less aclverse e fects.
(R ef Tripathi-61"1599)
Disadvantages of regular heparin compared to LMWH: Write adverse effects fr om above.

Q. What do you mean by low dose heparin? (CU -I 5J u)

Q. "Low dose heparin is used for prop hylaxis & high dose for treatment of established thrombosis"-
justify'. (DU- I OJ)
Ans.
For treatment of established thrombosis, (eg, acute pulmonary emboli, Ml, DVT), larger doses of h parin are
often required during the first few days because of binding to a variety of acute phase proteins, such as factor VI II
and von Willebrand factor, and increased hepari n clearance. La rger doses of hepa rin also prov ide im mediate
anticoagulation .

For prophylaxis of thrombosis, immediate anticoagu lation is not requ ired. So, low dose heparin is used for
prophylaxis. Low-dose prophylaxis is achieved with subcutaneous adm ini strati on of heparin , 5000 un its every 8-
12 hours .
(Ref Kutzung- 1Jth C'dition)

Q. Compare & contrast LMWH and traditional/conventional/unfractionated heparin. (RU- 1SJu, l3Ju, SU-
l 4J, 12J) /
Q. · ~om pare & contrast standard & low molecular weight heparin as an ticoagulant. (CU-1 SJ u, RU-091)
 . HI Ph armaco logy
Bl ueprmt 628
Q. Differentiate between' LMWH and UFH (unfractionated heparin), (CU -0~M; SU-08J) . "
-Q. Co~unGe t~~.cl~nica,I status of low molecular w~ight heparin with unfract10nated heparm. (DU-1 JJu)
An's./
I)ifferences between LMWH and traditional/conventional/unfractionated heparin
/

Traits • ,: \I I· ·. ' LMWHeparin I Unfractionated heparin .;,,..:

1. Molecu lar weight 45 00 Dalton l 2000 n;.i ltnn
-
2. Monosaccharide unit 15 40 -
3. Effect on APTT No Prolonged -
4. Plasma protein binding Less More
5. Pharmacokinetics More pred ictable Unpredictable
6. Plasma t112 _Longer Shorter
-
7. Bioavailability More Less
8. Activity -
Inhibits factor Xa Inhibits factor Ila, !Xa, Xa
9. Dosing interval Less freq uent (Once or twice a day) More frequen t
10. Monitoring Not requ ired Required (by APTT)
11. Use More convenient to use Less convenient
12. Suitability Su itable fo r outpatient. Not suitable fo r outpat ient
13. Thrombocytopen ia Less frequ ent More freq uent
14. Hemorrhagic complications Lower incidence Hi ghe r incidence

Q. How would you manage a case of bleedi ng from excessiv an ticoagu lant action of heparin? (RU-l 5Ju)
Ans.
Man agement of bleeding from excessive anticoag ulant i:i ction of hepari n:
1. Stop heparin
2. Inj. protamine sulfate:
• When infused slowly, it comb ines ionically wit h heparin to form a stable. I : I inactive complex.
• Dose of protamine sulfate: I mg fo r every I 00 units of heparin administered .
3. Close monitoring of the activated partial thromboplastin time (A PTT) is necessary in patients rece ivi ng
heparin .
(Ref Lippincolt 's-61"!30J)

Warfarin
Q. Explayt' mechanism of action of warfari n. (DU-17.1, RU-1 6.l u, 14Ju,05S, CU-04J, SU-08J u,07J)
Q. l)iscuss how wa rfarin acts as anticoagulant. (DU- !4J)
Q ~7{uss the mec ha nism of action of clicumarol? (RU-03S, SU-03 J)
Q. 70w does orally acting anticoagu lant produce their action? (CU-06S)
'.A.9'S,
echanism of action of warfarin/ clicumarol/ oral anticoagulant: The vi tam inj$-~peQ~ent factors 11, VII , IX
and X are produced as inactive proteins. These fac tors are rich in glutam ic acid (Gia) res idues, whi ch must be
further carboxy lated to enable the proteins to maintain an active tertiary structure. The carboxylase enzyme
responsible fo r th is in the liver requires vitamin K as a co-factor. Vitamin K is converted to an epoxide in this
reaction and must be regenerated to its active form by a reductase enzyme. This reductase is inhib ited by warfarin/
dicumarol, which res ul ts in inhibition of the carboxylation cyc le and is the basi s of the anticoagulant effect of
coumarins.

Warfarin / dicumaro l - inhib its vitam in- K epox ide redu ctase - Inhibition of convers ion of vitamin-K epox ide to
its active form - Inhibits carboxylation of glutamic acid residues in fac tors II , Vil, IX & X - No activati on of
facto rs II, YII, IX & X - Anticoagulant effect.
 629 Drugs used to treat the diseases of Blood

·. , GI ~ -- GI

~ ca 1
• c;;~ ~
ca:')-,
Inactive factors 11, VII , ~---------
IX and X Ac1I va tEJ d factors II, V II ,
IX and X

&
!e
I Warlarfn I
Figure. The role of vitamin Kin clotting and the mechanism of action ofwarfarin.
(Ref Davidson's medicine-22nd)

Q. Why are oral anti-coagulants indirectly acting? (DU-09Ju)

Ans.
Warfarin exerts its anticoagulant effect by inhibiting vitami n-K epoxide reductase enzyme wh ich resu lts in
decreased synthesis of vitamin K dependent clotting fac tors. As warfa rin / ora l anti coagulants do not exert their
action by direct interference in the coagulation cascade, they are also call ed indirect acting anti-coagu lants.

Q. Why there is a delay in the mechanism of action ofwarfarin? (SU-071)

An s.
Delay in anticoagulant action of warfarin: Warfarin inhib its vitarnin-K epoxide red uctase enzyme. As a result,
the synthesis of vitamin K dependent clotti ng factors (factors ll, VII , IX & X) is dec reased. There is an 8- to 12-
hour delay in the action of warfarin . Its anticoagulant effect results from a balance betwee n paitially inh ibited
synthesis and unaltered degradation of the four vitamin K-dependent clotting fac tors. The resulting
anticoagulation is dependent on their degradation half-lives in the circulation . These half-lives are 6, 24, 40, and
60 hours for factorsV T("lX; x ; and fl, respective ly. Larger initial doses of warfa rin hasten the onset of the
anticoagulant effect.
(Ref Katz ung- 13th)

pharmacokinetics of warfarin. (SU-07 J)

l>ha rmacokinetic properties of warfarin :

1. Route: Oral
2. Bioavailability: I 00%
3. Onset of action: At least 8-12 hours after adm ini stration .
4. Duration of action: 3 - 6 days.
5. Plasma Protei n Binding: 99 % is bound to al bum in
6. Volume of distribution : Low
7. Plasma half life (t 112 ): 36 - 48 hours
8. Metabolism: Liver
9. Excretion: Ki dney
I 0. Others: It crosses pl acenta & it may secrete in breast mi lk.
(Ref Katzung- 13th: friplllhi-6'"160 1)

Q. Write down the indications of oral anticoagulants. (DU -09Ju)

Pharmacology-8 1
 ,
/ HI
Blueprint I
Pharmacology 630
91~cntion t.hc indications of warfarin. (RU-05S, SU-031)
A r)).
Indications of oral anticoagulants/ warfarin:
I. Myocardial infarction (Ml).
2. Deep vein thrombosis
3. Hip arthroplasty
4. Fractured femur operation
5. Pulmonary embolism
6. Systemic embolism
7. Mitra! stenosis with embolism
8. Transient ischemic attacks
9. Atrial fibrillation
10. Heart failure.
(Ref Katzung-1JthJ

Q. Wf te down the adverse effects of oral anticoagulants. (DU-09Ju)

Q. »'hy warfarin is not suitable in pregnancy? (DU-1 IJu)
Q<Write down adverse effects of warfarin therapy. (DU-171, CU-141, RU-0JS; SU-031)
Ans.
'Xdverse effects of warfarin:
-..........; I. Bleeding disorders: Bleeding is the commonest complication of warfarin therapy. Hemorrhage is most
likely to occur in the alimentary and renal tracts, and in the brain in those wi th cerebrovascular disease.
2. Skin reactions: purpura, ecchymoses, hypersensitivity, rash and alopecia.
3. Skin necrosis due to a mixture of hemorrhage and thrombosis occurs rarely where induction of warfarin
therapy is over-abrupt and/or the patient has a deficiency of protein C or protein S.
4. Infarction of the breast, fatty tissues, intestine, and extremities.
5. Hemorrhagic infarction in venous th rombosis is caused by warfarin-induced depression of protein C
synthesis.
6. eratogenests:
·arm crosses the placenta readily and can cause a hemorrhagic disorder in the fetus.
• The drug can cause a serious birth defect characterized by-
:, Skeletal disorders (5%) (bossed fore head, sunken nose, foci of calcification in the epiphyses).
:, Absence of the spleen.
:, CNS abnormalities (microcephaly, cranial nerve palsies).
Thus, warfarin shou ld never be administered during pregnancy.
(Ref Bennett & Brown-1l ' + Katzung-1 Jth)

Q. How will you manage warfarin toxicity?

Q. What
I
is the antidote of warfarin toxicity? (RU -03S ; SU-03J)
Ans.
Management of warfarin toxicity: Excessive anticoagu lant effect and bleecling from warfarin can be reversed
by-
!. Stopping the drug
2. Antidote: Oral or parenteral vitamin K (phytonad ione)
1

3. Fresh-frozen plasma
4. Prothrombin complex concentrates
5. Recombinant factor Vila (rFVIIa).
(Ref Kar:ung- 1Jth)
 631
) · ·c·iscs
Drugs used to treat thc d1s '
of Blood
Q. Write down monitoring of warfarin therapy. (RU -0JS; SU-0JJ)
Ans. .
Moni~oring of wa~farin ~herapy: Monitoring of therapy is by the prothrombin time . Usuall y th e tcst_ is carried
out with a standardized th1omboplast111 anatne result is expressed ast ie ntcrnation al Norm~11iscd Ratio (INR).
Normal range of INR:
( fo r a healthy person is 0.9-1.3.
, fo r people on warfarin therapy, 2.0-3.0.
• higher in patients with a mechanical heart valve.
(Ref Bennett & Brown- I I th)
Nice to know
lntemational normalized ratio (INR): It is the ratio of the prothrombin tim e in the patient to that in a normal (non-
anticoagulated) ~~rson- takmg account of the sensitivity of the thromboplastin used. INR reliably re.fleets the degree of
prothrombm act1vily.
The result (in seconds) for a prothrombin time performed on a normal individual will vaty depending on what type of
analytical syS tern it is performed. The INR was devised to standardize the results. The INR is the ratio of a patient 's
prothrombin tim e to a normal (control) sample, raised to the power of the ISi (International Sensitivity Index) value for the
analytical system used

INR=
PTtest J
ISi
( PT normal
Interpretation: A high INR level such as INR=5 indicates that there is a high chance of bleeding, whereas if the INR=0. 5
then there is a high chance of having a clot.

Q. Mention the contraindications of anticoagulants.

Ans.
Contraindications of anticoagulants
I. Hemato logical: Pre- existing bleeding tendency li ke
• Hemophilia
• Purpura
• Thrombocytopenia
• Active bleeding
2. Cardiovascular:
• Long standing hypertension
• Infective endocarditis.
3. Neurological :
• Stroke due to intracranial hemorrhage (within 3 wks)
• Recent surgery: Brain or eye surgery
• Lumbar puncture or regional block
4. Renal impairment
5. Pregnancy (Oral anticoagulant crosses the placental barrier - Dicumaro l syndrome)
6. Hypersen si tivity reaction (Heparin)
7. Alcohol dependence .
8. Active pulmonary TB
9. Ulcerati ve les ions of GIT
l 0. Threatened aborti on.

Q. How does heparin differ from warfa rin? (DU-07 Ju,SU-08Ju,CU -0 l S)

Q. Compare the mechanism of action & possible adverse effects of wa rfarin & heparin. (CU- I2J,09Ju )
Q. Compare & contrast heparin & warfarin as anticoagu lant. (DU-07Ju/J , - I6Ju; RU-061; SU-09Ju)
Ans.
 632
ces between heparin & warfarin:

. { Only in vivo .
5. ··Plasma ti~,, Shorter Larger .
-6. .PPB . Less
Hinh Low
Ra id within-5.:-10 inin .

- 1O; Placental :barrier Cannot cross ·can cross

Absent .... ·' .· Pre.sent
of No ne.ed ·.. ;N'eede~ .' >
-. •' .,, ' r' l •y' •

Renal

(Ref Tripathi-61 1/604;

Q. Mention the drug interaction of oral anticoagulant (warfarin).

Ans.
Drug interaction of warfa rin :
A. Drugs that potentia te warfarin action :
1. Dru gs that inhi bit hepatic drug
• Cim etidi ne
metabolism
• Chloramphenicol
• Ciprotloxacin
• Metro nidazole
• Ami od arone
• Ketoconazole
• Fluconazole
2. Drugs that inhibit platelet • NSA!Ds (as pirin)
functions • Carbenici ll in
• Moxalactam
3. Drugs that displace warfari n • NSA!Ds (aspiri n)
from albumin
• Ch loral hydrate
4. Drugs that inhibit red uction of • Cephalosporins
vitamin K
5. Drugs that decrease • Broad spectrum antibiotics- (ciprofl oxac in, sul fo namides,
availability of vitamin K tetracyclines, amox,icill in, ampic illin)
 633 Drugs used to treat the diseases of Blood
8 . Drugs that inhibit warfarin action
1. Physiological / disease state • Pregnan cy
• I lypoth yro id is m
2. Vitamin K
3. Drugs that induce drug • Rifampi cin
metabolizing enzymes • Ca rbamaze pine
• Ba rbitu rates
• Gri seoful vin
4. Drugs that decrease absorption • Col estyramine
(Ref Rang & Dale 's-Hth)

Fibrinolytic Thrombolytic dru s

Q. Mention the 1brinolytic / thrombolytic drugs. (DU-1 6Ju ,07Ju; CU- l 4Ju, RU -1 41, l 2Ju, I IJ ,08Ju )
Q. Short ot . Fibrinolytics. (SU- 15Ju)
Ans.
Fibr' o tic I thrombolytic drugs: Acute thromboembol ic disease may be treated by the admi nistration of agents
tfi: activate the convers ion of plasm inogen to plasmin- a serine protease that hydro lyzes fi brin and , thus,
dissolves clots.
~ Streptokinase
"2 . Alteplase
3. Uroki nase
.A:-:" Tissue plasminogen activator (t-PA)
Reteplase
6. Tenecteplase

' First generation : Strepto kinase

_ Second generation: Alteplase
lThird generation: Reteplase

Q. Explain the mech anism of action ofstreptokinase. (RU -14J,12Ju,1 IJ ,08Ju)

Q. Explain he role of streptokinase in acute ischem ia. (SU-141)
Q. Explayi the pharmacological basis of the use of streptokinase in the ma nagement of acute myocardial
iofa ction. Enumerate the alte rn ative to streptoki nase in this clinical condition. (CU-06M)
I
Q. ;Sh rt note: Streptokinase. (DU-1 2J, RU- I SJ)
rfs.
echanism of action of streptokinase:
Streptokinase combines with plasminogen
t
Streptoki nase-plasm inogen complex
t
Conversion of plasminogen to pl asm in
t
Degradation of fi brinogen, fibrin , clotting facto rs V & VII by plasmin
t
Disso lution of clot in the em bo lus or th rombus
t
Re-openin g of the bl ood vessel.
 BlueprintTM Pharmacology 634
l
Increased blood flow to the myocard ium .
l
Relief of myoca rdial ischemia / infarction.
(R ef L ippincou 's-6thJ
Plasminogen
Activation Inh ibition
Various stimuli

er
Blood - - - - . Blood -©- ~ Antlactivato rs
proactlvator activator

t-PA, urokinase -e.- ~ Aminoacc_aproic

id
Streptokinase

~ -0-
Proactivator
~ J Plasmin I

Deg,adatlon + [Thtombln I\ Fibdn split

pro ducts . - Fibrinogen _ _....,_. Fibrin - - products

Fig. Schematic rep resentation of th e fibrinolytic system . Plasmin is the active jibrinolytic enzyme. Several
clinically usefu l activators are shown on the leji in bold. Anistrep lase is a combination of streptokinase and the
proactivator plasminogen. Aminocaproic acid (right) inhibits the activation of plasminogen to plasmin and is
useful in some bleeding disorders. (t-PA , tissue plasm inogen activator.)
(Ref Katzung-l 3th edition)
Q. Men on the indications of streptokinase? ( RU- l 2Ju)
?;t,; tion the indications of thrombolytic/fibri nolytic drugs. (RU-I 41, 1 I J)

~ ~ catio ns of streptoki nase:

I . Ac ute myocard ial infarction (ST e levated M I, w ith in 12 ho urs of on set of pa in)
2. Acu te p ul mona ry e mboli sm
3 . Severe deep ven o us t hrombos is:
• S uperior venacaval synd rom e
• Ascending thrombophleb itis
4. Pe riph era l vascular disease
5. Occ luded arte rio-venous shunts.

(Ref Lippinco/1 's-6th)

Q. Mention th e role of streptokin ase in lliD . (SU-1 JJ)
Q. Explain the pha rm acological basis fo r th e use of Streptoki nase in th e ma nageme nt o f ac ute Ml.
Enume rate the alternatives to Streptoki nase in th is clini cal co nd itio n. (CU-06M )
An s.
Use of streptokinase In MI: Id ea ll y stre pto kin ase (thrombo lyt ics) s hould be admi n istered as soon as possib le
afte r the o nset of sympto ms. Th ey ac t to d isso lve th e thro m bus, salvage the myoca rdi um , and lim it th e ex te nt o f
dam age.

Alternate to streptokinase :
• Alte plase
• Re te plase
 635 Drugs used to treat t h c• d'. · of Blood
isc ascs
• Tissue plasminogen activator (tPA)
• Trecteplase
• Recombinant prourokinase

Q. Wr!te down) he ~dv_ers~ effects of streptokinase. (RU-I 2Ju,08Ju, SU-05M)

Q. Wnte & V11 the hm1tahons of fibrinolytic drugs . (RU- I 4J)
Ans.
Adv effects of stre tokinase:
I. Bleeding disorders : due to dissolution of haemostatic plugs by elevated leve ls of pl as m in .
2. Hypersensitivity reaction : Streptokinase is a foreign protein and is antigeni c. Fever, rash & rarel y
anaphyl axis occur.
3. GIT: Nausea, vomiting
4. Multiple micro-emboli
5. Cardiac arrhythmias from reperfusion of ischemic areas.
(Ref Katzung-1 Jth)
/

Q. Meytion the contraindications of streptokinase?

Ans.
Cmfi raindications of strep to kinase:
) . Recent trauma.·
t ,,,2 / Recent surgery (within 6 months).
y Hemorrhagic stroke .
4. Severe hypertensi on.
5. Active bleeding peptic ulcer di sease .
./
Y Aneurysm .
r:
1 Bleeding disorder.
8. Acute pancreatitis.
9. Diabetes mellitus.
(Ref Tripathi-6t11/ 607 & 608)

Fibrinol tic 'inhibitors··: _

:j:iru.·s·used to sto·
., . .. ~ . bleedin
Q. ~~e f e drugs used to stop bleeding.
Q. 73i'e
the anti-fibrinolytic drugs.

Dru~ ~ used _to stop ~lee~in g/ Fi_b rinol~tic inhi~itor~/ Anti-fibrino~.yt~c .~ r~~s: ~ J\~
./-1. Ammocapro 1c ac id / epsil on ammocapro1c ac id (EACA) - . ., --:. 6 \..,__,.),
;;:;;;, Tranexamic acid (an analog ofaminocaproic acid). __..:::>-r -' t O 1. '~">' '-~
j

"3 ._/P rotami ne sulfate (antidote of heparin) , -, . . 9.- , ~ -""'

.4. Vitami n K 1 / phytonadione (antidote of warf arin) _ ~ · , -,.,. 't ": c, c~ ." <'"'J:_.~ i => ~ 0 ' -~ - \.'.
5. Aprotinin (s erine protease inhibitor) . -. ~ ,-v - . . : 7- __:_ . ~ ,,..,. ~,-,- '-"--
f ' .\ ·..---.. t.J '::::r -:'l- '° l) (Ref Lippinco fl 's -6th)
1

Q. W/ ite down the mechanism of action of aminocaproic acid/ tranexa mic acid .
A,1;{
Mechanism of action of aminocaproic acid / tranexamic acid : Arni nocaproic ac id and tra nexamic ac id are
synthetic inhibitors of fibrin olysis.
Aminocaproic acid/ Tranexamic acid
l
Competiti vely inhibits the bind ing of plasm inogen and t-PA to fi brin
l
 HI
I
Blueprint Pharmacolog)' 636
Thus inhibits plasminogen activation
!
No plasmin
!
No degradation of fibrinogen , fibrin, clotting factors V & VII.
!
Bleeding is stopped by the action of these clotting factors and fibrin .
/1,
(Ref Katzung- /3 + Bennet & Brown-// th)

Q. What are the indications of aminocaproic acid/ tranexamic acid?

iy11s.
r- Ly+t-vJ _ 0 ~Lr~ J' \

l4:idications of aminocaproic acid / tranexamic acid:

I . Adjunctive therapy in hemophilia
2. Overdose of fibrinolytic drugs (streptokinase / urokinase / alteplase)
3. Prophylaxis for rebleeding from intracranial aneurysms
4. Postsurgical gastrointestinal bleeding and postprostatectomy bleeding, after tonsill ectomy, tooth
extraction in hemophilic patient, uterine cervical conisation.
5. Bladder hemorrhage secondary to radiation- and drug-i nduced cystitis
6. Gynecological: Abruptio placenta, post-pa1ium hemorrhage (PPH) & ce1iain cases of menorrhagia.
7. After cardio-pulmonary bypass surgery.
8. Recurrent epistaxis, ocular trauma & bleeding peptic ulcer disease.
9. Thrombocytopenia: To reduce the risk of hemorrhage.
/ (Ref Katzung-13th; Bennett & Brown-l /1h)
J; 2Yntion the adverse effects of aminocaproic acid/ tranexamic acid.
~ erse effects of aminocaproic acid / tranexamic acid:
I. Intra-vascular thrombosis.
2. CVS: Hypotension, bradycardia & arrhythmia.
3. GIT: Nausea, diarrhea, abdominal discomfort.
4. Headache, giddiness.
5. Myopathy
6. Nasal stuffiness.
(R~f Katzung-13th)
Contraindication of aminocaproic acid/ tranexamic acid : The drug should not be used in patients with-
]. Disseminated intravascular coagulation
2. Genitourinary bleeding of the upper tract, eg, kidney and ureters, because of the potential for excessive
clotting.
(Ref Katzung-1 Jth)
' . '\ -· ,-
A
,[\ .\
-te
..'
p ,.
,_\
. ·e··1scs of Blood
637 Drugs used to treat t he cI is • · ·
~ . l, ....,.. / \,l ) --.: I l "w ~,, . \ J ,_,,, L
·_,"-// lil .fo IW.ll@ilfli@ ii§
Lipoproteins: Fou r major groups of plasma lipoproteins have been identified :
"-- '· Chylomicrons : Transport dietary TG , cholesterol and cho lestery l esters from intestine to th e peri phera l ti ss ue.
2. Very low density lipoproteins (VLDL): Transport TG from liver to periphera l ti ssue .
3. Low-density lipoproteins (LDL): Transport cholesterol from liver to periphera l tiss ue:
4. High-density lipoproteins (HDL): Transport cholesterol from periphe~al ti ssues ui the li ver (Reverse choleSlerol
transport). ·

Classifica tion of Hyperlipidemia / Dyslipidaemia ·

Disease Elevated lipid results Elevated CHO risk
lipoprotein
Predo minant hypercholesterolaemia TC±TG LDL ± VLDL +
• Familial hypercholesterolaemia TC ±TG LDL± VLDL +++
• Hyperalphalipoproteinaemia TC HDL --
Predominant hypertriglyceridaemia TG VLDL ± LDL Vari able
• Lipoprotein lipase deficiency TG >TC Chylo micro n ?
• Fami li al hypertriglyceridae mia TG +TC VLDL + Chylo '.)

Mixed hyperlipidem ia TC+TG VLDL + LDL Variab le

• Familial combined hyperlipidemia TC and/or TG LDL and VLDL ++
• Dys betalipoproteinaem ia TC and/or TG IDL ++ +
(R ef Davidson 's medicine-22nd)

Desirable Borderline to High Hig h

mg/dL (mmo l/L) mg/dL (mmol/L)
J6tal cholesterol < 200 (5.2) 200-239 (5.2-6.2) > 240 (6.2 )
/4DL cholesterol < 13 0 (3.4) 130- 159 (3.4-4 .1 ) > 160(4. 1)
HDL cholestero l > 60 (1.55)
/ Men > 40(1.04)
Women > 50(1.30)
y(iglycerid es < 120(1 .4) 120- 199(1 .4-2.3 ) >? 00(2.3)
/
(Ref Kca::ung-1 Jrh)

Q Enl'st t~ lipid lowering agents. (DU-I 6Ju , RU-l 3Ju, 11.!u, CU- l 4J, l 2Ju)
st,i mportant /clin ica lly used lipid lowering age nts. (DU - l 4J , l 2/ l OJu)
egorize drugs used in hyperlip idemia/d ysli pidemia. (C U-l 2J, RU-I 2J u)
iJ.Jia me the statin preparations used as hypolip idem ic agent. (RU-07J)
Q:'Name four lipid lowe ring agents. (DU -l 7M)
Ans.
Lipid lowering agents:

A. Predominantly cholesterol lowering agents:

l . HMG-CoA redu ctase inhibito rs (Statin s): • Lovastat in

(lc holeslerol .1ynlhesis & j LDL ca7crbolisrn • Atorvastatin
. Flu vastatin
• Pravastatin
• Sim vastati n
• Rosuvastatin
2. Cholesterol absorption inhibitors , Ezetimibc

Pharmacology-82
 TM
Blueprint

-
,, J.
Pharmacolo<?;Y
b,

~Bile acid-binding resin!--_

-
~
638
v(
/

Co lestipol
• Cholestyramine
• Colesevelam
-
A. fNiacin (Vit-B3)
-
B . Predominantly TG lowering agents:
~

I . r ibrates· / fibric acid derivatives • Gemfibroz il

I
1.,-, Fenofibrate
•_,,,. Bezafibrate
2. Highly poly-unsaturated long- • -- Eicosapentanoic acid
chain n-3 fatty acids • Docosahexanoic acid
(Ref Davidson 's m edicin e-22nd; Lippincott 's-6th)

Blood Gut

Acetyl-CoA

I
R esins

Fig. Sites of action <~( HMG-CoA reductase inhibitors, niacin , ezetimibe, an d resins used in treating
hyperlipidemias. LDL receptors (R) are increas ed by trea tmenl 1vi1h res ins and Hlvf G - C oA recluc/ase inhibitors.
(Ref K a tz ung- 13th)

Atorvastatin
Q. Short note: Atorvastatin . ( DU- l 4 Ju, 11 Ju, l OJ)
Q. Short note: Statin . (RU- I SJ)
A ns. Wr ite in brieffrom below.

Q. How does statins decrease serum cholesterol leve l? (DU-1 7 M , RU -1 2 J u, l l Ju)

Q. Write down the mechanism of action of statin. (DU-1 6 Ju , l 4J)
Q. Write down the mech anism of action & indications of ator·vastatin . (DU- l 2/ 1OJ u)
Q. Write down the mechanism of action fluvastatin. ( RU - l 3Ju)
Q. Write down th e mechanism of action simvastatin. ( C U- l 4 J )
Q. Explain the role of atorvastatin in heart disease/IHD . (SU - l 3J . l 2Ju)
 I ~
'2-{_~,'- L\'" ,, ~\(Y\(_ (c ti;:, _ _ _:r f 'J'·JO Cl..,..~ -

/, / s·\" n 639 Drugs used to treat the diseases of Blood

An; ( / .
st
Mechanism of action of Atorvastatin / Fluvastatin / Simvastatin /HMG CoA rcdu ctasc inhibitors I atms:
• Inhibition of HMG CoA reductase: All Stati ns have strong affi nity for HMG CoA reductase enzyme. 50
they c01_npete effectively to inhibit HMG CoA reductase enzyme - Block the rate li miting step of cho leS tero 1
synthes is-> !Cholesterol synth es is - t VLDL - tLDL.
• Increase in LDL receptors : Depletion of intra-ce llular cho lestero l due to decrease in its synthesis - jCe ll
surface LDL-receptor-> j Binding of LDL with its receptor & jlnternalization occ urs - jCatabo li sm LDL
- tPlasma cho lestero l.
(Ref Lippincoll 's-6th)

Nice to know
Tlterapeutic Uses & Dosage: HMG CoA reductase inhibitors (atorvastatin) are usefitl in lowering plaSma
cholesterol levels in all types of hyper/ipidemia.

Q. Why statins are preferred to adm inister in the even ing? (RU- I 3Ju)
Ans.
Statins are preferred to administer in the evening: Because cholestero l synthesis occurs predominantly _at
night, reductase inhibitors- except atorvastati n and rosuvastatin-should be given in the evening if a single daily
dose is used. Absorption generally (with the exception of pravastatin) is enhanced by foo d.
(Ref Katzung-13/h)

Q. Wrz
·te dz:t
z adverse effects of statin. (DU-14J) ~ I , o:-~..\--o-:. -, c >~ ;1 ~(_ \ ~

Q. What e e adverse effects of atorvastatin? (DU -I OJ u)

Ans.
Adve1s e fects of statins/ atorvastatin: Serious side effects are rare (we ll below 2%)
1

I . Liver fu nction : Biochemical abnormalitie of li ve function may occur. So, li ve funct ion should be
eval uated periodically.
2. Muscle: Myopathy, mya lgia, myositis & rhabdomyolys is (rare ly).
3. Drug interaction: May increase warfarin level, th us increasing bleedi ng tend ency. So, it is important to
evaluate prothrombin tim e frequent ly.
(Ref Lippincott 's-6th)

Q. Mentio e contraind ications of statins / ato rvastatin.

Ans/
\C~ rhindications of statins:
fI. Pregnancy or women who are likely to become pregnant
2. Nursing mother.
2
3. Children & teenagers.
(Ref Lippinco/1 's-6/h)

Fenofibrate
Mechanism of Action: These agents func tion primarily as li gan ds fo r the nu clear tran script ion receptor,
peroxisome pro liferator-activated receptor-a lpha (PPAR-a). They increase lipo lysis of li poprotein triglyceride vi a
lipoprotein lipase (LPL) resulting in decrease in tri glyce ri de in pl asma. Intracell ular lipo lysis in ad ipose ti ssue is
decreased. Leve ls of VLDL decrease . Only mod est redu ctions of LDL occur in most pat ient . HDL cholestero l
increases moderately.

Indication:
I. Hypertrigl yceridemi as in whi ch VLDL predominate
2. Dysbetalipoprotei nem ia
3. Hypertri glyceridemia th at resu lts from treatment with viral protea e inh ibi to rs
(Ref Katzung-l 3rh)
~~:.::,_.:.:.:.:;:.:::.;:;.=.s~---~;._---------------
TM
Blueprint Pharmacology 640

Q. What are the adverse effects of fibrates/fenofibrates'!

Ans.
Adverse effects of fibrates / fenofibrates:
I. GIT: Mild GIT disturbances.
2. Muscle: Myalgia, myopathy, myositis.
3. Biliary tree: Increases risk of gall stone formation
4. Abnormal liver function tests
5. Drug interaction: Increase warfarin level, thus increasing bleeding tendency .
(Ref lippincou 's-6th)

Q. What are the contraindications of fibrates/fenofibrates?

Ans.
Contraindications of fibrates/fenofibrates:
I. Pregnancy
2. Lactation
6. Renal failure
7. Hepatic failure
8. Pre-existing gall bladder pathology.
(Ref Lippincoll 's-6th)

Nice to know
Characteristics of antihyperlipidemic drug families
Type of drug I Effect on LDL I Effect on HDL I Effect on .triacylglycerols
Statins 1111 it ll
Fibrates 1 iti JJJJ
Niacin 11 iiii Hl
Bile acid-binding resins !H 1' Mi nimal
(Cholestyramine)
Cholesterol absorption inhibitors l 1' l
(Ezetimibe)
(Ref Lippincott 's-6th)
 641 Drugs used to trea t th c, d'is·casc•s
' of Blood

Hematinics (Fe, Vit-B 12 , Folic Acid)

Ei·yt~~·opoiesis: Erythropoiesis means the process of formation of erythrocyte under normal physiological
cond1t1ons. It starts in the 3rd week of intrauterine life.

Essential nutrients and factors required for normal erythropoiesis: They are as fol lows:
I. Iron
2. Vitamin 8 12
3. Folic acid
4. Hemopoietic growth factors, eg, erythropoietin.

Anemia: Anemia means a deficiency of hemoglobin, which can be caused by either too few red blood cells or too
little hemoglobin in the cells.
(Ref Guyton-l 2thl -120)

Q. List hem at' nics. (DU-15J , RU-I IJ, SU-09J)

Q. Lis o monly used hematinics. (CU-14J)
Q. s ematinic drugs. (DU- I IJ,09Ju)
rite anti-anemic drugs. (CU- I I Ju; RU-12J)
Ans:
Hematinic drugs: Hematinics are the drugs which increase erythropoiesis resu lti ng in increase in the number of
R8C or hemoglobin content or both and ultimately correction of anemia.

List of hematinics / anti-anemic drugs:

I. Iron preparations
2. Vitamin B12-preparations
3. Folic acid preparations
4. Hematopoietic growth factors, eg, Erythropoietin
. ""( "!--1 7:)-~•

Ans.
Hematinics safe during pregnancy:
__
Q. Name the hematinics used during pregnancy. (RU -1 OJ) ">
......_
I. Iron preparations: lron salts (oral) & iron dextran (IV or IM) both are safe.
2. Folic acid.
3. Vitam in 812-

IRON
I I
Total body iron is 3-5 g (40-50 mg/kg) (male > female).

e pharmacokinetics of iron. (CU- I I Ju)

1
• Average dietary iron contents: 10 - 15 mg/day (Dietary iron remain · in the fe rric rorm (Fc ' )
• Amoun t of daily abso rption: Abo ut 5- 10% o.r dietary contents (0 .5-1 mg/clay)
• Form of absorption: Iron i · exclus ively absorbed in ferrous (Fc 2 · ) fo rm .

Iron transport: re is transported in the plasma by bi ndi ng with tra11sfc rrin (an a-globulin) that specifica ll y binds
with two molecules of Fe 2'.
 . TM Ph armaco I og)'
Blueprmt 642
Stora0 c of iron-
~

Fo rms of storage iro n )".' Fcrrit in

/ Hacmos icl crin
Site of storage / · Reticul o-encl othcli al ce ll s: Sp leen, li ver, bone marrow .
,._/ Hepati c parenchymal ce ll s
,,-3·_ Skeleta l muscles .

Impo rtance of ferritin level: Ferriti n is detectab le in serum . Since the ferr it in present in serum is in equilibr iu m
wi th storage fe rritin in RE ti ssues, the ·'seru m ferri ti n leve l" can be used to estimate total body Fe stores.

Elimination of Iron:
/ There is no mechanism fo r Fe excretion.
';,----- small amo'tints are lost in the faeces by exfol iati on of intestinal mucosa! cell s.
• Trace amou nts are excreted 111 btle, unne & sweat.
1H
(Ref Katzung-J 3th + de Gruchy-5 138-40)

Q. How ?r~ ron preparations are absorbed from GIT? (DU -06M ; RU - I4Ju,09Ju,06/05S)
Q. HO\ r ,n is absorbed from GIT? (CU-l 6Ju, 14J)
Q. D s ribe mechanism of Iro n absorption . (CU-l 6J)
Ai ·
2 2
bsorption of oral iron preparations: Oral iron preparations contain iron in the ferrous (Fe +) fo rm. Fe ' 1s
solub le and is readily absorbed. Iron crosses the luminal membrane of the intestina l mucosa! cel l by two
mechanisms: active transpo11 of ferrous iron and absorption of iron com plexed with heme. The divalent metal
transporter, DMTI , effi ciently transpo1i s ferro us iron across the lum inal membrane of the intestinal enterocyte.
Together with iron spl it from absorbed heme, the newly absorbed iron can be acti ve ly transported into the blood
across the basolateral membrane, pro bably by the transporter IREG I, also known as f~1-ropo~~ . Excess iron can
be stored in the mucosa! cell as ferr itin, a water-soluble comp lex consisting of a core of fer ric hydrox ide covered
by a shell of a specialized storage protein called apoferritin.
(R~f' Katzung-13th)
Brush
bo rder
Intestinal Enterocyte Blood
lumen

Heme - - - ~ \
~ 2 ~
Fe2+ --> Fe2+ , Fe2+

----
/2+ Fe3+-ferrilin
I
i
fe3 +
i
Jshed Fe3"'-TF

Fig. Absorption qf ora/ iron (Ref Ganoni-2-lth edition)

 643 Drugs used to treat the diseases of Blood
e ribe th e factors that can hasten & retard the absorption of the oral iron preparations from th e gut.
U- I lJ ,09/08.lu)
s.
Factors affecting iron absorption :
Factors/conditions incrcasin!! absorntion Factors/conditions dccrcasin!! absorption
I . Iron defi ciency anemia & oth er anemia
l . Malabsorption syndrome
2. Pregnancy
2. Partial or total gastrectorny
3. Growinob aoe b
3. Tannin (in tea)
4. Vitamin-C
4. A hi gh phosphoru s di et (bread, ce reals & milk)
5. Meat
5. Salts of ph osphate, bi carbonate. phytates
6. Citric acid
6. Phytic acid (cereals)
7. Sugar
7. Drugs: Antacid, tetracycline, L-dopa, cipron oxaci n,
8. Am ino acid
desferrioxam ine.
9. A low phos phorus diet

Q. Name the different iron preparations. (RU-\6J,13 ,1 JJ ,09Ju, SU-121)

Q. Name the or I iron preparations. (DU-16Ju,10J,06M; CU-11J ,09/09Ju,06M; RU-17J,14J , 10J,06S)
Q. Name 3 or iron preparations. (DU-16J)
Q. Enu e te the parental iron preparations. (RU-14Ju)
Q. N he drugs in microcytic hypochromic anemia . (RU-061)
o t note: Oral iron preparations. (SU-15Ju)

A. Oral iron Tablet form ~ Ferrous sulfate

preparations \
• Ferrous fum arate
/" Ferrous gluconate
~ Ferrous succinate
• Ferro us glyci ne-S0 4
Liquid form T FeS 0 4 pediatric mi xture
,,,.-- Polysaccharide iron com plex
Sustained release form y Slow-Fe
', /s ytron
• Na-Fe edetate
/
B. Parenteral iron IV iron • Iron dextran
preparations ,.. Iron sucrose
IM iron Iro n dextran
>
• Jron sorbito l citric acid
(Ref Katzung-J2th/585)

te own the adva ntages & disadva ntages of oral iro n preparations . (DU-1OJ )
ention the advantages of differe nt formulations of iron. (DU-03J)
Ans.
Advantages & disadvantages of di ffe rent for mu lations of iron : Ora l tab let, IV and lM inj ec ti ons.
I .Advan~age~~ . .~--E·t'.': <,· .• ' Disadvantages •',_! . '\ . '

Oral iron l . Easy to adm inister I. Daily admin istration need ed

preparations: 2. Good pat ient co mpli ance 2. Blackeni ng of stoo l may confuse /
Tablet 3. No pain & scar mark. mi sguide as black tarry tool.
3. Anemia recovers slowly. o, can' t be given
to establi h the qui ck recovery of Fe store.
4. Can ' t be stored.
 Blucp rm· tn 1 PluI rr nacologyM. 644
Eli. · I . Ca n be 0oivL:n in small children and f. It stains th e tee th .
I
adults who prefer thi s.
Parenternl iron l. '' Daily administrati on is not needed f ,,,.. Not easy to ad mini ster.
pre pa rations .y., Quick recovery from anemia is ·,5.. Pain & blac kening or th e inj ecti on site .
poss ible. / /J . Patient 's complian ce is not good .
l),(' Gi en to pati~nts ~or wl~om iron can't 4. Haemopo ietic respon se is not qui cker th an
be absorbed trom 111test1n e. that of oral preparation .
4. Can be given to patients who can't be 5. Ionized salts are un su itable for parenteral
relied on to take it. preparations.
5. Patients with intolerable gut
symptoms.
6. No blackening of stool.

; ote: E/irix is the sweetened aromatic solution of alcohol and water, serving as u vehicle fo r medicine.

Q. What are the indications of iron therapy? (DU-01 J,CU-06M/S, RU-06S ,SU-05S)
Q. Mefon the indications of oral iron therapy? (RU-13J)

j~
Wliere is iron therapy needed? (DU-06M )
hat are the indications of parenteral iron therapy? (RU-1 4Ju)
s:
dications of iron therapy: Iron therapy is indicated in the treatm ent or prevention of iron deficiency anemia.
Iron deficiency anemia occurs in the following cond itions where iron therapy is needed-
Inadequate intake I. Nutritional deficiency:
• Ignorance & poverty
• Repeated pregnancy
• Milk injury & improper feed ing of the baby
2. Gastrectomy
3. Coeliac disease
4. Tropica l sprue
Increased demand I. In chi ldhood: Duri ng the peri od of growth, mostly between 6-24 months.
2. Menstruation.
3. Pregnancy.
4. Lactation.
Excessive blood loss I. Hookworm infestati on
2. Hemorrhage: Acc idental & surgical
3. Peptic ulcer disease
4. Bleeding hemorrh oids
5. Ruptured esophagea l varices
6. Ca stomach
7. Ca co lon
Defective utilization I . Ma labsorpti on syndrome
2. Parti al or total gastrectomy
3. Gastrojejunostomy
4. Chronic di arrhea
5. Ach lorhydria

!ndicatio~s of Parenteral Iron Therapy: Parent era l th erapy should be reserved for patients with doc umented
iron defi c1en? \~ho are_ unabl e _to tolerate or absorb ora l iron and for patien ts wit h ex tensi ve chron ic an emia who
cann~be mamta1n ed with ora l iron alone. Thi inc ludes pat ient with -
1/ Ad ~anced ~hronic renal di_seas~_rcqu irin g he1~odia lys is and treatment with crythropoiet in
;2. Vanous postgastrectomy cond1t1ons and previous small bowe l resection
 645 Drugs used to treat the diseases of Blood
_. 3. Inflammatory bowel di sease involving the proximal small bowel , and
4: Malabsorption syndromes.
(Re/' KutzunY,-l 2th/5 H5)

Q. How woJld you treat a case of iron deficiency anemia? (DU-I SJ, 11 J,09Ju , RU-06J , U- 11 Ju )
Q. EnumCfate the principles of Iron therapy. (CU-I 6Ju)
Ans. / /__ . . .
Trea · ent of a case of 1ro~ d Clf.Jl~ anemta IDA / rinci >les of Iron thera :
:_j:- Orally administered errous sulfate ·s the treatment of choi ce for iron deficiency.
2. Ferrous sulphate 20 mg · -10urly ( 195 mg of elementa l iron per day) is more than adequate and should
be contmue or 3-6 months to rep ete iron stores.
3. lf ferrous sulphate causes yspepsia an a tered bowel habit, its dose can be reduced to 200 mg I2-h_9 urly
or a switch to ferrous luconate 300 mg 12-hourly (70 mg of elemental iron per day). -
yttaemoglobin should rise by 1 g/dL everfi-=-rn days and a reticulocyte count will be in creased within a
.: week.
5. A failure to respond adequately may be due to non-compliance, continued blood loss, malabsorpt ion or an
incorrect diagnosis.
6. Patients with malabsorption or chronic gut disease may need parenteral iron therapy with single or
multiple doses of intravenous iron dextran or iron sucrose. Doses required can be calculated based on the
patient's starting Hb and body weight. Observation for anaphylaxis fol lowing an initial test dose is
recommended
(Ref Davidson's-22 nd; Goodman & Gillman-I 2'h)

Q. Describe the total dose infusion for parenteral Iron therapy. (CU-161)
Ans.
Total dose infusion for parenteral Iron therapy: Doses required for total dose infusion for parenteral iron
therapy can be calculated based on the patient's starting Hb and body weight.
Iron to be injected (mg) = Total iron deficit
=Bodyweight [kg] x (Target Hb - Actual Hb) [g/dL] x 2.4 + 500mg

500 mg is added to replenish the iron store if body weight> 35kg.

Most adult patients require a cumulative dose of elemental Fe of at least 1 g.

Q. A 26 year old woman came to the OPD with the comkplaint of rapid heart rates and easy fatigabili ty,
laboratory workup reveals low hemoglobin and microcytic red cells. Discuss your diagnosis; write
causes & treatment of this clinical cond ition. (SU-13 Ju)
Ans.
Diagnosis: Iron deficiency anemia (IDA).
Cause: Most common causes of IDA in this young woman are-
!. Menstruation.
2. Pregnancy.
3. Lactation.
Treatment: Oral iron therapy.

Q. Mention the side effects of iron therapy? (DU-09Ju)

Q. What are e adverse/toxic effects of oral iron therapy? (RU -17 J, I4J, I3J ,06S/J,04J; SU-0SS)
Q. enti the adverse effects of parenteral Fe therapy. (CU-06S ; RU-04S ,03J)
Q tion the adverse effects of ferrous sulphate. (RU-16J)

Adverse effects of iron therapy:

A. Adverse effects of oral iron therapy:
1. Nausea & vomiting (sometimes causes intense nausea & vomiting).

Pharmacology-83
 Bl ueprmt
. TM· pharmacology 646
2. Epigastric discomfort
3. Abdomi nal cramps
4. Constipation
5. Diarrhea
6. Black stoo l: This has no clinical significance, but it may obscure the diagnos is of continued GIT blood
loss.

B. Adverse effects o(parenteral iron therapy:

• Intra-muscular iron therapy:
I . Local pain
2. Tissue stain ing around the injection site
• Intra-venous iron therapy:
I. Headache
2. Light-headedness
3. Fever
4. Arthra lgia
5. Nausea & vomiting
6. Back pain
7. Fl ushing
8. Bronchospasm
9. Urticaria
I 0. Anaphylaxis (rarely).
(Ref Katzung-13th)
Q. Mention how long time ferrous sulphate is to be used to correct anemia and why. (RU-161)
Q. Why oral Fe therapy should be continued fo r more than 3 months? (CU-091)
Ans:
Treatment with oral iron should be continued for 3-6 months after correction of the cause of the iron loss. This
corrects the anemi a and replenishes iron stores.
(Ref Katzung- l 3th)

Q. How you assess the effective iron therapy? (DU-161,1OJ)

Ans.
As ment of effective iron thera :
I . Clinical assessment: Clinically effective iron therapy is assessed by improvement of anemia and the
patient's complaints such as weakness, tiredness, appetite, lethargic cond ition etc.

2. Biochemical assessment:
• Hemoglobi n percentage (Hb %) will be increased.
• Serum iron and serum ferritin level will be increased
• Serum iron binding capacity will be decreased .
3. Increase in reticulocyte count

t are the manifestations of acute iron toxicity? How do you manage the condition? (DU -05J, RU-
J, I IJ, CU-06M)
ns:
Acute iron toxicity: Acute iron toxicity is seen almost exclusively in yo ung children who acci dentally ingest iron
tablets. Although adults are able to tolerate large doses of oral iron w1 ou senous consequences, as few as 10
tablets of any of the commonly avai lable oral iron preparations can be lethal in young ch ildren .
_____.
Clinical features of acute iron toxicity:
I. Necroti zi ng gastroenteritis
2. Vomit ing
- 3. Abdominal pain
647 Dru~s used to treat the diseases of Blood

4. Bloody diarrhea
5. Shock
6. Lethargy
7. Dyspnea
8. Metabolic acidosis
9. Coma and death.

Management: Urgent treatment is necessary.

I. Whole bowel irrigation should be performed to flush out unabsorbed pills.
2. De eroxamme, a potent iron-chelating compound, can be given systemically to bind iro n that has already
been absorbed and to promote its exc1 etio11 in urine and feces.
3. Appropriate supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shoc.:k must al so be
provided.
(Rel Katzung- 13th)
 . Tl\!
Blucpnnt 648
Pharmacology
Vitamin B12
· · B 12 (cobalamm)
V 1tam111 . serves as a cofactor ,or
/:". severa
. I es sential. biochemical
. reactions
. in humans.. Althougl1
deficiency of vitamin 8 12 due to an inadequate supply i~ th e d1_et is_ unus~al , defic~ ency of B1 2 1~ adults:-
especially older adults-due to inadequate absorption of dietary v1tarnm B1 2 1s a rel atively common and easily
treated disorder.

Active forms of vitamin B 12 :

1. Deoxyadenosylcobalamin
2. Methylcobalamin

Q .. What are the causes of vitamin B12 deficiency?

Ans:
, Common causes of vitamin B12 deficiency:
1. Pernicious anemia
2. Partial or total gastrectomy
3. Malabsorption syndrome
4 . Inflammatory bowel disease
5. Small bowel resection.
(Ref Katzung-l 3th)
/
ft What are the diseases caused by vitamin B 12 deficiency?
Ans:
Diseases caused by vitamin B 12 deficiency:
1. Megaloblastic anemia.
2. Combined degeneration of spinal cord (Demyelination of large nerve fib ers of the spinal cord especially
of lateral column).
3. Gastrointestinal symptoms.
(Ref Katzung-l 3th)

Q. Name the drugs used in megaloblastic anemia. (RU-05M)

Ans:
Drugs used in megaloblastic anemia:
I . Vitamin B 12
2. Folic acid

Q. Name the vitamin B 12 preparations.

A

Route
1. Parenteral vitamin B 12 - ~-
, anocobalamin I/Mor SIC
-- - - - - - + - -----+-- - - - ~ ~ - - - - - - - ---,
droxocobalamin
2. Oral vitamin B 12 anocobalamin Ora l! I 000 mc o/ml/day

Q. "Folic acid should be administered only after excl usion of Vit-8 12 deficien cy anemia"- Explai n. (CU -091 )
Q. A physician has treated with folic acid of a megaloblastic anemic patient due to vitamin B 12 deficiency.
What will be the hazards? (RU-06J)
Ans :
Rationale of using Folic acid after confirming the diagnosis: People with mega lob lastic anemia clue to vitam in
B12 deficiency are usually identified because of signs and symptoms of anemia, which typi ca lly occur befo re
neurologic symptoms. So if this anemia is corrected by ad ministration of fo lic acid, vitam in 8 12 defi ciency will
remain undiagnosed and will be more and more severe. The most dangero us hazards of thi s defi ciency-
 649 Drugs used to treat the diseases of Blood
:;iernyelination o~ nerv_e fibers:' & "combined degeneration of spinal cord" may develop. But folic ac id does no!
prevent the potentially irreversible neurologic damage caused by vitamin B12 deficiency.
So, before treatm~nt the exact cause of megaloblastic anemia should be detected- whether it is due to vitamin 812
or folic acid deficiency.
(Ref Kalzung-I ]!h)

Folic acid
RDA: 100-200 µg/day
Source: Green leafy vegetables, whole grains, cereals, liver, kidney, yeast and eggs.
Active from: Tetrahydrofolate

Functions of folic acid:

1. Tetrahydrofolate (THF) can carry one-carbon units attached to N-5 (formyl, formimin o, or methyl
groups), N-10 (formyl group), or bridging N-5 to N-10 (methylene or methenyl groups) for the
biosynthesis of a variety of bio-molecules (eg, methionine. serine etc).
2. It is ·nvolved in tyrosine metabolism and formation of RBC.
(Ref Harper 's-26'hl493)
C e of folic acid deficiency:
Inadequate dietary intake
2. Defective absorption
3. Use of anticonvulsant drugs (phenobarbitone, phenytoin)
4. Increased demand eg, in pregnancy.

Q. Briefly d'sc ssthe deficiency feature of folic acid.

Ans.
D fie' n 7 feature of folic acid: Fol ic acid deficiency 1s probably the most common vitamin defi ciency,
observed primarily in the pregnant women.
1. Megaloblastic anemia.
2. Growth failure
3. Neural tube defect in the fetus eg, spina bifi da, anencephaly (when deficiency in pregnant mother)
4. Glossitis
5. Gastrointestinal disturbances

Indications of folic acid:

1. Megaloblastic anemia due to fo lic acid deficiency
2. Pregnancy
3. Hemo lytic anemia
4. Live diseases
5. Spina bifida
6. Skin di seases
7. Alcoholic

Contra-indication:
I. Megal oblastic anemia due to vitamin B 12 deficiency
2. Folate dependant cancer.
Blueprint™ Pharmacology 650

Erythropoietin therapy
Erythropoietin: It is a 34-39 kDa glycoprotein & is a human hematopoietic growth factor & produced by the
peritubular cells of kidney .
Function: Erythropoietin stimulates erythroid proliferation & differenti ation by interacting w ith erythropoietin
receptors on red cell progenitors and thus increases red cell production.

Recombinant human erythropoietin

/. Epoetin alfa (administered three times a week)
2. Darbepoetin alfa (administer ed weekly)
3. Methoxy polyethylene glycol epoetin beta (administered as a single I V or SC dose at 2-week or monthly
intervals)

Indications: Erythropoietin is useful for the treatment of anemia in the following cases-
1. Chronic ren al failure.
2. Cancer patients treated with myelosuppressive cancer ch emotherapy
3 . Primary bone marrow disorder (eg, aplastic anemia, myeloproliferative and mye lodysplastic disorders,
multiple myeloma and perhaps other chronic bone marrow ma li gnancies).
4. HIV-infected pati ents treated with zidovudine
5. Patients schedul ed to undergo elective, noncardiac, no nvascu lar surgery: It red uces the need fo r
transfusion in these pat ients.

Adverse effects: Hy pertension, thrombotic comp lications (most serious), flu- li ke syndro me, hype rsensitivity.
(Ref Katzung- 13th)

Nice to know
Blood doping: Highly competitive athletes have used epoetin a/fa to increase their hemoglobin levels ( "blood
doping ") on the hope that this will increase oxygen d elivery to m uscles and improve p erformance. Unfortunately,
this misuse of the drug has been implicated in the d eaths of several athletes and is strongly discouraged
Erythropoietin is one of the drugs banned by the International Olympic Committee.
(R ef Katz ung -13 11, edition: Goodman & Gilman- I 2 11, edition)

Plasma volume expander

Q. Enlist the plasma vo lume expander.
Ans.
Plasma volume expanders:
1. Human albumin
2. Dextran
3 . Degraded gelatin polym er (polyge line)
4 . Hydroxyethyl starch (HES)
5. Polyvinylpyrro lidone (PVP)

· -1dications:
1. Severe bum
2. Severe hypovolemic shock including severe hemorrhage.
3. Severe traum a.
4. Extensive tissue damage .

Contraindications: Severe anemia, cardiac failure, pulmonary edema, renal failure .

(Ref Tripathi-6r1'/ 622-623)
- <>SI

MCQ
Drugs used to treat. t·hc. d.isc,
, ascs of
· Blood

Q. Low dose aspirin- (DU-I 6J) Q. Warfarin is used in the following clinical
a) binds with COX enzyme reversibly situations- (DU - IJ.lu)
b) inhibits TXA2formati on in platelet a. angina pectoris.
c) may c use GIT bleeding b. implant prosthdic valve .
d) inhibits PGl 2formation c. chronic atri al fibrill ation.
e) blocks platelet ADP receptors d. venous th romboe mbolism.
a. F, b. T, c. T. d. T, e. F e. cerebrovascular stroke.
a. F, b. T, c. T, d 7~e. F
Q. Adverse effect of heparin includes- (DU-15Ju)
a. alopecia Q. The following dugs prevent platelet
b. hemorrhage aggregation- (DU- IJJ)
C. DIC
a. clopidogrel.
d. osteoporosis b. ticlopid ine
e. myopathy c. warfarin.
a. T, b. T, c. F, d. T, e. F d. low dose heparin.
e. streptokinase.
a. T, b. T, c. F, d. T, e. F
Q. Following are the manifestations of Folic acid
deficiency: (CU-l 4Ju)
a) Enteritis. Q. The following are adverse effects of heparin
b) Spina bifida in the offspring. therapy- (DU-I 3J)
c) Loss of ankle reflex a. osteoporosis.
d) Hallucination ' b. alopec ia.
e) Glossitis c. thrombocytopen ia.
d. diarrhea.
a. T, b. T, c. F, d. F, e. T
e. fetal cleft palate.
a. T, b. F, c. T, d. F, e. T
Q. Drugs preventing platelet aggregation are-
(DU-141)
Q. The advantages of LMWH include- (DU- 11 J)
a. clopidogrel
a. No need of monitori ng (T)
b. streptokinase
b. Low ri sk of bleeding (T)
C. ticlopidine
c. High pl asma protein binding dru g (F)
d. warfarin
d. Admini stered IV (T)
e. dipyridamol.
e. Less bioavailabil ity (F)
a. T, b. F, c. T, d. F, e. T
Q. The follo~ing drugs prevent platelet
Q. Following are the fibrinolytic agents- (DU-
aggregation- (DU-I0Ju)
13Ju)
a. Clopidogrel (T)
a. alteplase.
b. Ticlopidine (T)
b. streptokinase.
c. Warfa rin (F)
C. clopidogrel.
d. Low dose asp irin (T)
d. tranaxaemic acid.
e. Streptoki nase (F)
e. abciximab.
a. T, b. T, c. F, d. F, e. F
Q. Rega rding warfarin- (DU- \ 0Ju)
Q. Enoxaparin- (DU-13Ju)
a. It is given orally (T)
a. is a LMWH. b. It can cause bleeding (T)
b. is injected subcutaneously. c. It acts within 24 hours of admin istration (T)
C. requires intense monitoring. d. Its effect can be antagoni zed by pro tamine
d. bi oavai lability is less then HMW one. sul fate (F)
e. can cross the placental barrier. e. It causes fibr inolysis (F)
a. T, b. T, c. F, d. F, e. F
BlueprintTM Pharmacology 652
Q. Heparin- (DU- IOJ)
a. is effective if given orally (F)
b. can cause osteoporosis (T)
c. acts by inhibiting vit K dependent coagulation
factors (F)
d. may cause thrombocytopenia (T)

Q. Aspirin- (DU- I OJ)

a. inhibits PGs synthesis (T)
b. inhibits LTs synthesis (F)
c. can cause sodium retention & edema (T)
d. excretion can be enhanced by giving
ammonium chloride (F)
e. can cause premature closure of the ductus
arteriosus if given in late pregnancy (F)