Drugs affecting blood flow

What is hemostasis?

Bleeding prevention by fibrin formation and platelet aggregation

Difference between arteries and veins in thrombosis

Arteries have more platelets while veins have more fibrin

Drug categories that affect blood flow

• Anti-platelet drugs

• Oral anti-coagulants /anti-fibrin drugs

• Injectable anti coagulants/ thrombin inhibitors

• Thrombolytic drugs

Preferred drugs in arterial thrombosis

Antiplatelet drugs

What injured blood vessels release?

1. Thromboxane A2 - vasoconstrictor and platelet activator

2. ADP (adenosine diphosphate) - promote platelet aggregation

3. GP receptors ( GP lIb/IIIa ) - makes sticky ( Exteriorization)

4. Thrombin - convert fibrinogen to fibrin→platelet plug formation

Types of Antiplatelet drugs

1. Drugs acting on Thromboxane A2 - Aspirin

2. Drugs acting on ADP - Clopidogrel, Ticlopidine

3. Drugs acting on Gp IIb/IIIa - Abciximab, Tirofiban, Eptifibatide

4. Drugs acting on PAR-1 receptors of Thrombin - Atopaxar, Vorapaxar

What is the first antiplatelet drug

Aspirin

Normal platelet receptor involved in aggregation

GP IIb/IIIa

Substances released after vascular injury

• TXA2

• ADP

• Thrombin

Effect of platelet activation

Platelets become sticky and aggregate

Drug acting on ADP receptor

• Clopidogrel

• Ticlopidine

Drugs acting on GP IIb/IIIa receptor

• Abciximab

• Tirofiban

• Eptifibatide

Drugs acting on thrombin PAR-1 receptor

• Atopaxar

• Vorapaxar

TXA2 causes what effect on platelets

Platelet aggregation

PGI2 causes what effect on platelets

Inhibits platelet aggregation

Aspirin mechanism of action

Irreversible inhibition of COX

Prostaglandins / arachidonic acid pathway

Arachidonic acid pathway

1. Cell membrane phospholipids release arachidonic acid via phospholipase A₂ when cells are stimulated (injury, inflammation).

2. Arachidonic acid is metabolized mainly by two pathways: cyclo-oxygenase (COX) → prostaglandins/thromboxanes, and lipoxygenase (LOX) → leukotrienes.

3. In the COX pathway, arachidonic acid is first converted to unstable intermediates PGG₂ and PGH₂.

4. PGH₂ is the common precursor for several prostanoids, depending on the tissue-specific enzymes present.

5. In platelets, PGH₂ is converted to thromboxane A₂ (TXA₂) → promotes platelet aggregation and vasoconstriction.

6. In vascular endothelium, PGH₂ is converted to prostacyclin (PGI₂) → inhibits platelet aggregation and causes vasodilation.

7. In other tissues, PGH₂ forms PGE₂, PGD₂, and PGF₂α, which mediate inflammation, pain, fever, smooth muscle contraction, and other local effects.

ADP receptor on platelets

P2Y12 receptor

Irreversible P2Y12 inhibitors

• Clopidogrel

• Ticlopidine

• Prasugrel

Nature of clopidogrel and prasugrel

Prodrugs

Enzyme activating clopidogrel

CYP2C19

Effect of omeprazole on clopidogrel

Inhibits CYP2C19 and reduces effect ( because clopidogrel activated by CYP2C19)

Safest PPIs with clopidogrel

• Pantoprazole

• Rabeprazole

Faster acting ADP inhibitor

Prasugrel

Major risk of prasugrel

Hemorrhagic stroke

Contraindication of prasugrel

Stroke

Reversible P2Y12 inhibitors

• Cangrelor

• Ticagrelor

Strongest antiplatelet drugs

GP IIb/IIIa inhibitors

Example of Drugs acting on GP IIb/IIIa

• Abciximab

• Tirofiban

• Eptifibatide

Main action of thrombin

Generation of fibrin

Thrombin receptor on platelets

PAR-1 receptor

Effect of thrombin binding PAR-1

Platelet activation

Oral PAR-1 antagonist used clinically

Vorapaxar

PAR-1 antagonist not used

Atopaxar

Anti-platelet drugs preferred in which thrombosis

Arterial thrombosis

Antifibrin drugs are also called

Anticoagulants

Classification of anticoagulants

• Oral

• Parenteral / injectable

Oral anticoagulant group include

• Vitamin K inhibitors

• Direct thrombin inhibitors

• Factor Xa inhibitors

Drugs in vitamin K inhibitors

• Warfarin

• Dicumarol

Clotting factors requiring vitamin K to become active

Factors II ,VII ,IX ,X

Vitamin K function

• Gamma carboxylation of clotting factors II,VII,IX,X and activate them

• Activation of anticoagulant proteins C,S

Anticoagulant proteins activated by vitamin K

• Protein C

• Protein S

Enzyme inhibited by warfarin

VKOR (vitamin K epoxide reductase)

Initial effect of warfarin

• Hypercoagulable state / Dermal vascularnecroosis / increased clotting

• Occur for initial 1-2 days

Reason for warfarin induced hypercoagulation

Protein C deficiency

Warfarin complication causing skin necrosis

Purple toe syndrome

Properties of Warfarin

• Oral anticoagulant

• Inhibit vitamin k

• Need 4-5 days to produce action

• Mainly for maintainence purpose

• C/I in pregnancy →prevent osteocalcin action →Fetal warfarin syndrome → skeletal deformity (Microcephaly, Nasal hypoplasia, Microophthalmia)

• Monitered by PT/INR

Warfarin onset of action

4 to 5 days

Warfarin use

Maintenance therapy

Warfarin acts only in vivo

Yes

Warfarin contraindicated in pregnancy

Yes

Warfarin causes fetal syndrome

Fetal warfarin syndrome

Cause of skeletal deformity in fetus

Inhibition of osteocalcin

Features of fetal warfarin syndrome

• Microcephaly

• nasal hypoplasia

• microphthalmia

Monitoring parameter of warfarin

PT / INR

Why INR is preferred over PT

INR remains same across all labs but PT have different values in different labs

Effect of warfarin overdose

Bleeding

Four factor complex / Prothrombin factor complex contains which factors

• IIa

• VIIa

• IXa

• Xa

Treatment of choice for warfarin bleeding

Four factor complex

Alternative if four factor complex unavailable

Fresh frozen plasma

If both four factor complex and fresh frozen plasma unavailable then

Whole blood is given

Antidote for warfarin

Vitamin K

INR less than 5 management

Stop warfarin

INR 5 to 20 management

Stop warfarin and give vitamin K

INR more than 20 management

Stop warfarin and give four factor complex

Drugs increasing bleeding risk with warfarin

1. Enzyme inhibitors

2. Drugs displacing warfarin from PPB sites

3. Antimicrobials

4. Liver disease

Examples of enzyme inhibitors

• Erythromycin

• Ciprofloxacin

Drugs displacing warfarin from PPB sites

Sulfonamides

Antibiotic increasing bleeding with warfarin

• Cefoperazone

• Broad spectrum antimicrobial

Disease increasing warfarin effect

Liver disease

Drugs decreasing warfarin effect

Enzyme inducers

Examples of enzyme inducers

• Rifampicin

• Carbamazepine

Oral direct thrombin inhibitor

Dabigatran

Monitoring required for dabigatran

Not required

Antidote for dabigatran

Idarucizumab (monoclonal antibody)

Direct factor Xa inhibitors drugs

• Rivaroxaban

• Apixaban

• Edoxaban

• Betrixaban

Riveroxaban

pneumonic - RiverOXABAN

• River - Reversible

• O - Oral

• XA - Xa

• B - Blocker

• AN - Antagonist

Antidote for factor Xa inhibitors overdose

Andexanet alfa

Types of injectable anti-coagulants

• Indirect thrombin inhibitors

• Direct thrombin inhibitors

Injectable anticoagulants

Heparins

Indirect thrombin inhibitor example

• unfractioned Heparin (UFH)

• Low moleculer weight heparin (LMWH)

• Fondaparinux

UFH effect on clotting factors

Inhibits IIa and Xa

LMWH effect on clotting factors

Inhibits Xa more than IIa

Fondaparinux action

Only inhibits factor Xa

Route of heparin administration

Subcutaneous or IV

Onset of heparin action

Immediate (in acute conditions)

Anticoagulant of choice in pregnancy

Heparin

Monitoring of heparin

APTT

LMWH monitoring required

Usually not required

LMWH monitoring in renal failure

Anti-factor Xa assay

Antidote of heparin

Protamine sulfate

Heparin side effects mnemonic

Pneumonic - BOTHA

• Bleeding

• Osteoporosis

• Thrombocytopenia ( HIT )

• Hyperkalemia

• Alopecia

HIT occurs how many days after starting heparin

4 to 5 days

Feature of HIT

Thrombocytopenia with thrombosis

Treatment of HIT

Direct thrombin inhibitors

Difference in Warfarin and HEparin

Difference between warfarin and heparin onset

• Warfarin - slow

• Heparin - immediate

Warfarin pregnancy safety

Contraindicated

Heparin pregnancy safety

Drug of choice

Direct thrombin inhibitor (injectable)drugs

• Bivalirudin

• Argatroban

• Melagatran