Coagulants & anti coagulant Drugs

Drugs Affecting Coagulation;
Bleeding & Thrombosis
By:- Dr. Manish Pal Singh,
Associate Professor
1
AGRA PUBLIC PHARMACY COLLEGE,
ARTONI, AGRA, UP, INDIA

Some Important Terminology’s:
✓ Haemostasis - Limiting blood loss consequent to bleeding.
✓ Thrombus - A clot that “adheres” to a vessel wall.
✓ Embolus - Intravascular clot that “floats” in blood.
✓ “Detached” thrombus – Embolus.
2Source*- https%3A%2F%2Fslideplayer.com

Blood coagulation
➢ Blood coagulation involve complex interactions between the injured vessel wall;
platelets & coagulation factors.
3Source*- https%3A%2F%2Falevelbiology.co.uk
PROTHROMBINASE*

4Source*- https%3A%2F%2Fwww.quora.com

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Two In- vitro Tests for Coagulation Efficacy of Blood System

Coagulants:
❑ These are agents which promote coagulation and are indication in haemorrhagic
states.
6
Note*- Vitamin K2- (Produced by bacteria)- Menaquinones
Source*-https%3A%2F%2Fwww.youtube.com

VITAMIN K:
❑ In our body system it is fat soluble vitamin, required for synthesized of clotting
factors.
❑ ‘Dam’ (1929)- first describe that bleeding disorder in chicken by feeding
deficient diet.
❑ A similar vitamin was isolated (1939)- from “Alfalfa Grass” & labelled Vit. K1;
while that sea fish (sardine meal) was labelled k2
7
Source*-https%3A%2F%2Fwww.123rf.com%2Fphoto_83348596_chemical-
formula-of-vitamin-k-and-some-pills-close-up-

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Vit. K-
Naphthoquinone
Source-
green leaf,
spinach,
liver etc.
3-10 µg/day
Total req.
adult- 50-
100µg/day

➢ Vit. K acts as a cofactor at a late stage in the synthesis by liver of coagulation
proteins- (Prothrombin; VII; IX & X).
➢ Fat soluble form absorb by intestine via lymph & water soluble directly absorb
via portal blood.
➢ Deficiency of it founds in liver diseases like – jaundice ; superinfection by
antimicrobial uses.
➢ Market preparations are:-
➢ Phytonadinone “ KENADION” i.m injection (10 mg/ml)
➢ Menadione “ GYNAE”
9
Source*- https%3A%2F%2Fwww.unitedpharmacies.md%2FKenadion-Phytomenadione.

✓ Indications of Vitamin K:-
✓ Dietary deficiency
✓ Prolong antimicrobial use
✓ Malabsorption
✓ Liver disorders – Viral hepatitis
✓ Newborns (due to low level of Prothrombin)
✓ Overdose of oral anti-coagulants (Hypo-prothrombinaemia).
✓ Toxicity:-
✓ Rapid i.v. injection produces- flushing, sense of constriction in the chest
✓ Fall in BP
✓ Menadione can cause- haemolysis ( Patients with G-6-PD deficiency and neonates)
10

Anti-Coagulants
❑ Drugs that impede blood coagulation and prevent the occurrence or expansion
of a thrombus.
❑ These are drugs to reduce the coagulability of blood.
11
Source*-https%3A%2F%2Fwww.formularywatch.com%2Ffda-approval%2Fblockbuster-anticoagulant-

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Source*- https%3A%2F%2Fwww.acrosspg.com%2Fnotes%2Fpharmacology%2Fclassification-of-anticoagulants%2F&psig

Heparin:
✓ ‘McLean’- 1916- was discovered that liver contain powerful anticoagulant.
✓ Heparin its name due to found in “Liver”.
✓ Mainly it is present in all tissues containing “Mast cells”- (Lungs are the richest
source).
✓ Heparin used both in-vivo & in-vitro.
✓ Anti-thrombin III - Irreversibly inactivates thrombin & factor Xa
13
Source*- https%3A%2F%2Fwww.indiamart.com%2Fproddetail%2Fheparin-sodium-injection

➢ The heparin – ATIII- complex then binds to clotting factors of the intrinsic &
common pathways (Xa; IIa; IXa; Xia; XIIa & XIIIa) but not extrinsic system.
➢ Low concentration of heparin prolong aPTT without significantly prolonging PT;
high concentration prolong both.
14
Source*-http%3A%2F%2Fread.nxtbook.com%2Fmedreviews%2Freviewscardiovascularmedicin

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Source*-https%3A%2F%2Fwww.nejm.org

➢ Injection of heparin clears turbid post-prandil lipaemic- by releasing a
‘Lipoprotein-lipase’from the vessel wall & tissue (LIPAEMIA CLEARING).
➢ Heparin is a highly ionized molecule; not absorbed orally; i.v. injection prefer.
➢ But recent trials oral heparin in under ‘Phase-III’- trial (SNAC-Heparin).
➢ Doses of heparin i,.v. (5,000-10,000 U; {Children 50-100 U/Kg).
➢ ADR’s:-
➢ Bleeding due to over dose.
➢ Haematuria
➢ Thrombocytopenia
➢ Transient Alopecia
➢ Osteoporosis
16

Low molecular weight heparins (LMWH):-
✓ Can be administered s.c.
✓ Effects are consistent & dosing less frequent (Long t1/2 & elimin. By 1st
order kinetics)
✓ Do not prolong aPTT & CT (Response is predictable & monitoring not
required)
✓ Dose is given in mg (not in units) can be easily calculated on body weight
basis
✓ Chance of haemorrhage chance is less
✓ Risk of osteoporosis is decreased
17

Heparin Antagonist:- (Protamine Sulfate);
➢ Its low molecular weight protein obtained from the sperm of certain fish.
➢ Dose required 1 mg is needed for every 100 U of heparin.
➢ Indicated in the treatment of heparin induce bleeding
➢ Protamine is more commonly used when heparin action needs to be terminated rapidly;- Ex-
After cardiac or vascular surgery.
➢ Brand- “PROTA”- 50 mg in 5 ml inj.
18
Source*-https%3A%2F%2Fwww.omnia-health.com%2Fproduct%2Fprotamine-sulphate-injection-50mg5ml&psig

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Heparinoids :-
▪ Heparan Sulfate- found on cell
surface.
▪Danaparoid- Obtained from pig gut
mucosa (used in heparin induced
thrombocytopenia).
▪Leprirudin-recombinant preparation
of hirudin acts by inhibiting thrombin
directly
Source*-https%3A%2F%2Fsg.carousell.com%2Fp%2Fhirudoid-heparinoid-cream-

Oral Anti- Coagulants:
❑ Warfarin- was initially used as rat poison; it is now commonly employed oral
anticoagulant drug.
❑ Warfarin and its congeners acts as anti-coagulants only in vivo, not in vitro.
❑ They act as competitive antagonists of vit. K & reduce the plasma levels of
functional clotting factors.
❑ Competitively inhibits vitamin K epoxide reductase & inhibits the
posttranslational carboxylation of glutamate residues on vitamin K dependent
coagulation factors II (prothrombin), VII, IX, and X.
❑ The carboxylation is essential for the ability of the clotting factors to bind Ca++
& to get bound to phospholipid surfaces- necessary for coagulation.
20

21Source*- https%3A%2F%2Fwww.cambridge.org

❑ Recemic Warfarin sod.- the commercial preparation of warfarin is a mixture of
R (dextrorotatory) & S (levorotatory) enantiomers.
❑ The S form more potent than the R form.
22
Source*- http%3A%2F%2F119.9.73.171%2FUniwarfin-Warfarin-p-6349.

ADR’s:-
▪ Bleeding ( hematuria)
▪ Treatment (specific antidote- Vit. K1).
▪ Contraindications in- Pregnancy; in early pregnancy cause birth defects (Skeletal
abnormalities).
▪ Foetal Warfarin Syndrome- Hypoplasia of nose, eye socket, hand bones & growth retardations.
23
Drug Interactions:-
Source*-https%3A%2F%2Fwww.cmaj.ca%2Fcontent

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Source*-https%3A%2F%2Fwww.researchgate.net

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• Haemodialysis• Cerebrovascular
disease
• Unstable angina• Myocardial infarction

Fibrinolytics (Thrombolytics)
❑ These are drugs used to dissolve (lyse) clot (thrombi) to clear a occluded blood
vessels (CAD).
❑ In body system the enzyme “Plasminogen activator (t-PA), act as fibrinolytic
produced by vascular endothelium.
▪ Urokinase
▪ Streptokinase
▪ Anistreplase
▪ Alteplase
▪ Reteplase
▪ Tenecteplase
26
Clinically
Fibrinolytics

Mechanism of action:
27
Source*- http%3A%2F%2Fwww.pharmacy180.com%2Farticle%2Ffibrinolytics-(thrombolytics)

➢ Streptokinase- It is obtained from- ‘Streptococci’ group C. Antigenic- cause
hypersensitivity reactions.
➢ Urokinase- It is an enzyme isolated from human urine; now prepared from
cultured human kidney cells. Fever during treatment.
➢ Alteplase- rt-PA (recombinant tissue plasminogen activator) produced by
recombinant DNA technology from human tissue culture.
28
Source*- https%3A%2F%2Fwww.facebook.com%2FEMNote.org

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Uses of Fibrinolytics
Acute
myocardial
infarction
Deep vein
thrombosis
Pulmonary
embolism
Peripheral
arterial
occlusion
Stroke

Anti-Platelet Drugs
❑ These are drugs which interfere with platelet function and are useful in the prophylaxis of
thromboembolic disorders.
❑ Platelets express several glycoprotein on their surface.
❑ They are exposed when there is damage to vascular endothelium & interact with platelet receptor
protein.
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Source*- https%3A%2F%2Fwww.quora.com%2FWhat-is-the-function-of-the-blood-platelets

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Source*- https%3A%2F%2Fthoracickey.com%2Fantiplatelet-therapy

32Source*-https%3A%2F%2Fwww.researchgate.net%2Ffigure%2FFig-1-

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Uses of Antiplatelet drugs;-
▪MI - Low dose Aspirin
▪Unstable angina - Aspirin / Clopidogrel
▪ Coronary bypass implants
▪ Prosthetic heart valves
▪ Arterio venous shunts
▪ Venous thromboembolism
▪ Peripheral vascular disease
▪ Cerebrovascular transient ischemic attacks

Coagulants & anti coagulant Drugs

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