DRUGS AFFECTING COAGULATION,BLEEDING AND THROMBOSIS.pptx

DRUGS AFFECTING
COAGULATION,BLEEDING AND
THROMBOSIS( except antiplatelet)
DR. RANIT BAG
PGT IN PHARMACOLOGY, CNMCH

 Learn about coagulation cascade and coagulation factors
 How the blood clots are broken down
 What drugs can be used to regulate clotting
 How to rectify clotting deficiencies
Objectives

Terms
 Hemostasis(vasoconstriction +coagulation + platelet aggregation)
 Coagulation cascade and clotting factors
 Thrombosis
 Aptt, pt
 Antithrombin , Protein C & S
 Zymogens
 Scaffolding
 Disorders like Hemophilia, Deep vein Thrombosis, Ecchymosis, epistaxis etc
 CVA(cerebro vascular accident), ACS( acute coronary syndrome)

Commonly asked questions
1. Role of heparin in Ischaemic heart disease
2. Role of streptokinase in Acute myocardial infarction
3. Enumerate anticoagulants used for DVT
4. Low mol. Weight Heparin preferred over conventional heparin for
therapeutic uses
5. Heparin is useful both in vivo and in vitro-explain
6. Short notes- a)thrombolytic drugs, b)Warfarin Sod., c)
EACA/Tranexamic acid
7. Advantages of newer oral anti coagulants over warfarin

 Prevent coagulation (anticoagulants)
 Dissolve clots
 Prevent bleeding and hemorrhage - Hemostatic
 Overcome clotting deficiencies (replacement
therapies)
 Drugs preventing platelet aggregation
Classes of Drugs

Coagulants
Haemostasis(arrest of blood loss) and blood
coagulation involve complex interactions between the
injured vessel wall, platelets and coagulation factors.
For coagulation, a cascading series of proteolytic
reaction started by-
a)Contact activation of Hageman factor(Intrinsic
system)
b)Tissue thromboplastin(extrinsic system)

Clotting factors are of 3 types-
1. Contact Family (XII, XI, HMWK,
Prekallikrein)
2. Vt K dependent factors( II, VII, IX, X)
3. Fibrinogen family(I,V,VIII,XIII)
Liver produces all factors except III, IV and VIII

1.Vitamin k
Nature :- It is a fat-soluble dietary principle required for
the synthesis of clotting factors.
Chemistry and source :-Vit K has a basic naphthoquinone
structure, with or without a side chain (R) at position 3.
The side chain in K1 is phytyl; in K2 prenyl ;while in K3 there is no side
chain.
Dietary sources :-Green leafy vegetables, such as cabbage. spinach; and
liver, cheese etc.
Daily requirement :-Even 3-10 µg/day external
source may be sufficient. However, the total requirement
of an adult has been estimated to be 50-100 µg/day

Action :- Vt k helps in gamma carboxylation of glutamate
residue and activates coagulation factors II, VII,IX, X.
USE :-
1.Vt K requires in dietary deficiency
2.Vt K is administered in case of prolonged
antimicrobial therapy
3.Obstructive jaundice or malabsorption syndromes(sprue, regional ileitis,
steatorrhoea, etc.)

4. It is used in liver diseases (cirrhosis, viral hepatitis)
5. vit k( 1mg) i.m. soon after birth has been recommended
routinely. Some prefer administering 5- 10 mg
i.m. to the mother 4 -12 hours before delivery.
6. Haemorrhagic disease or the newborn can be
selectively prevented/treated by such medication.
Menadione (K,) should not be used for this
purpose
7. Overdose of oral (coumarin) anticoagulants is the most important indication of vit K.
Phytonadione (K1) is the preparation of choice,

Severe deficiency: 10 mg i.m followed by 5 mg 4 hourly;
bleeding generally stops in 6-12 hours, but normal levels of
coagulation factors are restored only after 24 hr. This dose of vit
K will block anticoagulant action for 7- 10 days.
Moderate deficiency: IO mg i.M. Followed by 5 mg once or
twice according to response.
Mild deficiency: Lust omit a few doses of the anticoagulant.

Adverse effects:-
1. Severe anaphylactoid reactions can occur on i. V. Injection of
emulsified formulation; this route should not be used
2. Menadione and its water-soluble derivatives can cause haemolysis
in a dose-dependent manner. Patients with G-6-PD deficiency and
neonates are especially susceptible.
3. In the newborn menadione or its salts can precipitate kernicterus:
(a) by inducing haemolysis and increasing bilirubin load.
(b) by competively inhibiting glucuronidation of bilirubin.
Glucuronide conjugation is, as such, inadequate in neonates.

2. Fibrinogen
 The fibrinogen fraction is synthesized from of human plasma
.
 It is employed to control bleeding in haemophilia,
Antihaemophilic globulin (AHG) deficiency and acute
afibrinogenemic states:
 It is given at dose of 0.5 g i.V.

3.Antihaemophilic factor
 It is concentrated human AHG (factor VIII) prepared from pooled human
plasma.
 It is indicated (along with human fibrinogen) in haemophilia which is due
to AHG deficiency.
 It is highly effective in controlling bleeding episodes,
 Its action is short-lasting ( I to 2 days).
 Dose: 5-10 U/kg by i.V. Infusion. Repeated 6-12 hourly

4.Desmopressin
 This synthetic peptide is a selective V2 agonist;
 It is 12 times more potent antidiuretic than AVP, but has negligible vasoconstrictor activity.
 It releases factor VIII and Von willebrand's factor from vascular endothelium and checks
bleeding in haemophilia and Von willebrand’s disease
 It is also longer acting because enzymatic degradation is slow; t½ 1- 2 hours, and the
duration of action is 8- 12 hours.
 Desmopressin is the preparation of choice for a ll Y2 receptor related indication s. The
intranasal route is preferred.
 Though bioavailability is only IO 20% . an oral formulation has been marketed with a
bioavailability of 1- 2%.

5. Adrenochrome
monosemicarbazone
 It is believed to reduce capillary fragility, controlling from raw
surfaces and prevent microvessel bleeding, e.g. epistaxis,
haematuria, secondary haemorrhage from wounds. Etc.
 Its efficacy is uncernain.
 Dose: I 5 mg oral, i.M.

6.Rutin
 It is a plant glycoside claimed to reduce capillary bleeding.
 It has been used in a dose of 60 mg oral bd/tds along with vit
C which is believed to facilitate its action.
 Its efficacy is uncertain.

7. Ethamsylate
 Ethamsylate reduces capillary bleeding when platelets arc adequate
 It probably corrects abnormalities of platelet adhesion, but does not mobilize fibrin
(not an antifibrinolytic).
 Ethamsylate has been used in the prevention and treatment of capillary bleeding
in menorrhagia, after abortion, epistaxis. Malena, hematuria and after tooth
extraction.
 Its efficacy is unsubstantiated, therefore not recommended now.
 Side effects are nausea, rash, headache and fall in bp (only after i.v Injection).
 Dose: 250- S00 mg tds oral/i.v

Local haemostatics (styptics)
 Local haemostatics (styptics) that are substances used to stop bleeding from a
local and approachable site.
 They are particularly effective on oozing surfaces, e.g. Tooth socket, abrasions, etc.
 Absorbable materials like fibrin (prepared from human plasma and derived as
sheet or foam). Gelatin foam, oxidized cellulose (as strips which can be cut and
placed in the wound).
 M.O.A :- It provide a meshwork which activates the clotting mechanism and checks
bleeding.
 Uses:- 1. Thrombin obtained from bovine plasma may be applied as dry powder to
use in hemophilas.
2. Vasoconstrictors like 0. 1 % ad r solution may be soaked in sterile cotton-
gauze used in broken tooth, epistaxis etc.
3. Astringents such as tannic acid or metallic salts are occasionally applied for
bleeding gums, bleeding piles, etc.

Sclerosing agents
 These are irritants.
 They cause inflammation. Coagulation and ultimately fibrosis.
 These are injected into haemarroids (piles} or varicose vein mass.
 They are used only for local injection.
 1. Sod. Tetradecyl sulfate (3% with benzyl alcohol 2%): 0.5-2 ml at each site.
SETROL 2 m l inj.
 2. Polidocanol (3% inj): 2 ml; ASKLEROL 2 ml inj.

1.Heparin
Chemistry and occurrence :-
 Heparin is a non-uniform mixture of straight chain rnucopolysaccharides with MW I 0,000
to 20,000.
 It contains polymers of two sulfated disaccharide units-
D-glucosamine-L-iduronic acid + D-glucosamine-D-glucuronic acid
 Heparin carries strong electronegative charges and is the strongest organic acid present
in the body.
 It occurs in mast cells as a much bigger molecule (MW ~75,000) loosely bound to the
granular protein.
 Thus, heparin is present in all tissues containing mast cells; richest sources are lung, liver
and intestinal mucosa.
 Commercially it is produced from ox lung and pig intestinal mucosa.

Actions
A. Anticoagulants :-Heparin indirectly activates plasma AT III by –
1. Providing scaffolding for the clotting factors (mainly xa and Ila) on one hand
and AT-Ill on the other, so that they interact with each other.
2. Inducing conformational change in AT-Ill to expose its interactive sites. A
specific pentasaccharide sequence, which is present in only some of the heparin
molecules, binds to AT III with high affinity to induce the conformational change needed
for rapid interaction with clotting factors.
B. Antiplatelet :-
Heparin in higher doses inhibits platelet aggregation and prolongs bleeding time.
C. Lipaemia cleaning :-Injection of heparin clears turbid post-prandial Iipaemic plasma by
releasing a lipoprotein lipase from the vessel wall and tissues, which hydrolyses
triglycerides of chylomicra and very low density lipoproteins to free fatty acids (FFAs).

Pharmacokinetics
 Heparin is a large, highly ionized molecule; therefore not absorbed orally.
 Bioavailability of s.c. Heparin is inconsistent.
 Heparin does not cross blood-brain barrier or placenta (it is the anticoagulant of
choice during pregnancy).
 It is metabolized in liver by heparinase and fragments are excreted in urine.
 After i.V. Injection of doses < 100 U/kg, the t½ averages 1 hr. It is prolonged to 4-
10 hrs in case of cirrhosis and kidney failure
 UFH is safer than LMW heparins or fondaparinux in kidney failure patients.

Adverse reaction
 Bleeding due to overdose is the most serious complication of heparin therapy.
 Heparin-induced thrombocytopenia (HIT) is another common problem(due to
formation of antibody against heparin-platelet complex)
 Transient and reversible alopecia is infrequent.
 Serum transaminase levels may rise.
 Osteoporosis may develop on long-term use of relatively high doses.
 Hypersensitivity reactions are rare; manifestations are urticaria, rigor, fever and
anaphylaxis.
 Patients with allergic diathesis are more liable.

Contraindications
 Bleeding disorders, history of HIT.
 Severe hypertension (risk of cerebral haemorrhage),
 Threatened abortion, piles, g.i. Ulcers (risk of aggravated bleeding).
 Subacute bacterial endocarditis (risk of embolism), large malignancies (risk of
bleeding in the central necrosed area of the tumour), tuberculosis (risk of
haemoptysis).
 Ocular and neurosurgery, lumbar puncture.
 Chronic alcoholics, cirrhosis, renal failure.
 Aspirin and other antiplatelet drugs should be used very cautiously during heparin
therapy.

Heparin antagonist
Protamine sulfate
 It is a strongly basic, low molecular weight protein obtained from the sperm of certain
fish.
 I mg is needed for every 100 u of heparin for the treatment of heparin induced
bleeding,
 Protamine is more commonly used when heparin action needs to be terminated rapidly,
e.g. After cardiac or vascular surgery.
Adverse reactions :-
 In the absence o f heparin, protamine itself acts as a weak anticoagulant by interacting
with platelets and fibrinogen.
 Being basic in nature it can release histamine in the body. Hypersensitivity reactions
have occurred.

Q. Low mol. Weight Heparin preferred over
conventional heparin for therapeutic uses
Advantage over M.O.A :-
I) LMWH selectively inhibits factor xa with little effect on IIa.
2) They act only by inducing conformational change in AT ill and not by providing a scaffolding
for interaction of AT ill with thrombin.
3) LMW heparins have smaller eftect on aptt and whole blood clotting time than unfractionated
heparin (UFH) with less chance of thrombocytopenia.
Advantage of pharmacokinetics :-
 Better subcutaneous bioavailability (70-90%) compared to UFH (20- 30%)
 Longer and more consistent monoexponential t½ (4- 6 hours)
 Laboratory monitoring is not needed; dose is calculated on body weight basis.
 Risk of osteoporosis after long term use is much less with LMW heparin.

Indications of LMWH
1.Prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in high-
risk patients undergoing surgery; stroke or other immobilized patients.
2. Treatment of established DVT.
3. Unstable angina (UA) and M l: they have largely replaced continuous infusion o f
UFH.
4. To maintain patency of cannula and shunts in dialysis patients.

Direct thrombin inhibitors
1. Bivaluridin :-
 20 amino acid peptide congener of the larger polypeptide
anticoagulant hirudin secreted by the salivary glands of leech.
 It is a specific a nd reversible DT I with quick onset a nd short
lasting anticoagulant action.
 Bivalirudin is indicated as an anticoagulant in patients
undergoing percutaneous coronary intervention (PC!)
 For STEMI. It is to be used along with an antiplatelet drug viz.
Aspirin and/ or clopidogrel or a glycoprotein llb/ la inhibitor
(Gpl).
 It can also be used in unstable angina (UA) and NSTEMI when
urgent or early PC! Is planned. It is specifically o f value in
patients at risk of HIT.

2. Argatroban :-
 This is a synthetic non peptide compound which binds reversibly 10 the catalytic site of
thrombin.
 Not to the substrate recognition site, it acts as a DTI.
 Administered by i.v. bolus (350 µg/kg over 3-5 min) followed by 25 µg/kg/min infusion.
 It produces a rapid onset short-lasting antithrombin action.
 Argatroban prolongs APTT and its dose is regulated by measuring INR. As such. Care
needs to be exercised while shfiting patients to warfarin prophylaxis.
 It is indicated for prophylaxis and treatment of thrombosis and for PCI in patients with
HIT or in those who arc al risk of developing I IIT.
 Argatroban is cleared by liver with a biological t½ of 45 min. Thus, it can be given 10
patients with renal disease

1.Vitamin K antagonists
Oral anticoagulant' refers to the warfarin-
like drugs which act by blocking synthesis
of clotting factors.
Mechanism of action :-
They competitively inhibit the enzyme vit
K epoxide reductase (VKOR) and interfere
with regeneration of the active
hydroquinone form of vit K which is a co
factor for gamma carboxylation of factor
II,VII,IX,X.

Adverse reactions
A. Bleeding as a result of extension o f the desired pharmacological
action is the most important problem
B. It causes ecchymosis, epistaxis, hematuria, bleeding in the g.I.t.
C. Intracranial or other internal haemorrhages may even be fatal.
Bleeding is more likely if therapy is not properly monitored, or when the
international normalized ratio (I R) exceeds 4, or interacting
drugs/contraindications are present.

Q.Advantages of newer oral anti
coagulants over warfarin
• Rapid onset and offset of therapeutic effect
• Short half life
• No laboratory monitoring required
• Fixed dosage guidelines depending on the indication
• Antithrombotic efficacy equal to/better than warfarin.
• Lower risk of bleeding compared to warfarin
• Fewer drug interactions.

DIRECT FACTOR Xa INHIBITORS
1. Rivaroxaban :-
 It is an orally active direct inhibitor of activated factor Xa
 Its anticoagulant action develops rapidly within 3-4 hours of ingestion and lasts for ~24
hours.
 It is largely metabolized, but also excreted unchanged in urine
 Plasma t½ is 7- 11 hours.
 It requires no laboratory monitoring of PT or aPTT.
 Use:- a)Prophylaxis anticoagulant used in venous thromboembolism following total
knee/hip surgery;
b) Rivaroxaban has also been found equally effective as warfarin for preventing stroke
patients with atrial fibrillation.
c) 2.5 mg/day for coadministration with aspirin and clopidogrel for prophylaxis of ACS.
Side effects:-Bleeding, nausea. Hypotension, tachycardia and edema.

Cont.
2. Apixaban :-
 This is another oral factor Xa inhibitor having properties and indications similar to
rivaroxaban.
 The oral bioavailability of apixaban is 85% and peak effects are produced in 3 hours.
 It is partly metabolized by CYP3A4 and eliminated in both faeces as well as urine.
 The plasma t½ is 12 hours.
 Use :- a)Prophylaxis of VTE following knee/hip replacement (dose: 2.5 mg BO)
b)prophylaxis of stroke in AF patients (dose: 5 mg 80).
c)Treatment of DVT and PE (dose: IO mg BO for 7 days followed by 5 mg 8D).
Drug interaction :-Drug interactions with inducers and inhibitors o f CYP3A4 are possible
and it should not be used in patients with hepatic or renal impairment.

ORAL DIRECT THROMBIN INHIBITOR
Dabigatran etexilate :-
 It is a prodrug which after oral administration is rapidly hydrolysed to dabigatran.
 This direct thrombin inhibitor which reversibly blocks the catalytic site of thrombin
 Though oral bioavailability is low i.e. enhanced by P-gp (efflux transporter)
inhibitors (verapamil, amiodarone, etc.)
 Plasma t½ is 14 hours and duration of action 24 hours.
 There is no drug interactions and any laboratory monitoring required .
 Use :-Prevention of VTE following hip/knee joint replacement surgery and
prevention of embolism and stroke in patients of atrial fibrillation.
 Side effects :- Bleeding, dyspepsia, ocaational hepatobiliary disorders.

Fibrinolytics
 These are d rugs used to lyse
thrombi/clot to recanalize occluded
blood vessels (mainly coronary artery).
 The fibrinolytic drugs are:
streptokinase, urokinase, alteplase (rt-
pa) reteplase, tenecteplase etc.
 M.O.A :-They are therapeutic rather
than prophylactic and work by
activating the natural fibrinolytic
System (SEE THE PICTURE)

Q. Role of streptokinase in Acute myocardial
infarction
 The chief indication for fibrinolytic therapy is STEMI
 These are the tissue plasminogen activators which forms plasmin from
plasminogen and plasmin degrades the fibrin . In this way they helps in recanalizes
the coronary artery and removes the plaque formation.
 Recanalization of thrombosed coronary artery has been achieved in 50-90% cases.
 In STEM! Fibrinolytics are an alternative first line approach to emergency
percutaneous coronary intervention (PC I) with stent placement.
 Best results are obtained if perfusion can be restored within the first hour (the
golden hour).

Uses of fibrinolytics
1. Acute myocardial infarction
2. Deep vein thrombosis (DVT) in leg, pelvis, shoulder etc.;
3. Fibrinolytic therapy is indicated in large, life-threatening pulmonary
embolism.
4. Fibrinolytics canalise - 40% limb artery occlusions.
5. Alteplase is approved for use in ischaemic stroke.

Contraindications
1. H/o intracranial haemorrhage
2. H/o ischaemic stroke in past 3 months
3. H/o head injury in past 3 months
4. Intracranial tumour/vascular abnormality/ Aneurysms
5. Active bleeding/bleeding disorders
6. Patients receiving anticoagulants
7. Peptic ulcer, esophageal varices
8. Any wound or recent fracture or tooth extraction
9. H/o major surgery within 3 weeks
10. Uncontrolled hypertension
11. Pregnancy

Antifibrinolytics
1. Epsilon amino-caproic acid (EACA) :-
 It is a lysine analogue which combines with the lysine-binding sites of plasminogen
and plasmin so that the latter is not able lo bind to fibrin and lyse it.
 It has been used in many hyperplasminaemic states associated with excessive
intravascular fibrin o lysis resulting in bleeding.
 The primary indication of EACA is to counteract the effect of fibrinolytic drugs and
bleeding in case of tooth extraction, prostatectomy, trauma, etc of the
hemophiliacs.
 EACA is active orally and can be infused i.V. As well. It is excreted by the kidney.
 Side effects:- Hypotension, bradycardia, arrhythmia, ureteric obstruction,myopathy
etc. Not used in renal impairment.

2. Tranexamic acid :-
 Like EACA, it binds to the lysine binding site on plasminogen and prevents its
combination with fibrin leading to fibrinolysis.
 It is 7 times more potent than EACA,
 It is preferred for prevention/ control of
• excessive bleeding due to fibrinolytic drngs.
• Cardio-pulmonary bypass surgery.
• Tonsillectomy, prostatic surgery, tooth extraction in haemophiliacs.
• Menorrhagia, especially due lo i uco.
• Recurrent epistaxis, hyphema due lo ocular trauma, peptic ulcer.
Side effects :- Nausea, diarrhoea. thromboembolic events, disturbed colour vision
allergic reactions etc. Thrombophlebitis occurs due to rapid injection.

Notes
 Please read the chapter from any standard text book
 Prepare the questions arrived in previous years
 Write the short notes according to 3-4 points(nature of drug, M.O.A,
pharmacokinetics, indications, side effects etc.)
 Read the topics on
A)Adverse effect and management of warfarin
B)Short details on LMWH drugs
C)Advantages of alteplase over Streptokinase
 Give flow charts or diagram for writing M.O.A of any drug
 For other informations ,please search from other sources(reference books, google,
slideshare etc)

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