(6) 33: Anticoagulant Drugs I

Blood clots — Know the difference

Arterial clots	Venous clots
White → platelet-rich	Red → fibrin/RBC-rich
MI, ischemic stroke	DVT, PE
Antiplatelets	Anticoagulants

Coagulation:

Factor Xa → thrombin (IIa) → fibrin → clot.

Coagulation problems

• DVT: Leg swelling, pain, redness, warmth.

• PE: Clot travels to lungs → sudden shortness of breath + chest pain.

• AFib: Blood stagnates in left atrial appendage → clot → ischemic stroke.

Anticoagulant drug

Warfarin (Coumadin)

Warfarin (Coumadin) - topics overview

• Class

• MOA

  • Vitamin K-dependent factors

• fun facts?

  • Delayed onset

  • hypercoagulability

• Bridging

• INR monitoring

• Toxicities - BST

• Interactions

• Warfarin reversal

• Clinical indications - AVM

• Patient counseling — KIMB

• Warfarin pharmacokinetics

  • Genetics

Warfarin (Coumadin) — Class:

Oral vitamin K antagonist (anticoagulant).

Warfarin (Coumadin) — MOA

Warfarin inhibits VKORC1 (vitamin K epoxide reductase)

→ ↓ active vitamin K recycling

→ ↓ γ-carboxylation of clotting factors

→ ↓ functional factors II (2), VII (7), IX (9), X (10)

• 🧠 1972 = factors 10, 9, 7, 2.

→ ↓ blood clot formation.

Also decreases proteins C and S (natural anticoagulants).

Vitamin K-dependent factors?

• 2, 7, 9, 10 + C/S.

  • 🧠 1972 = factors 10, 9, 7, 2.

Vitamin K-dependent factors

Which pathway?

• VII: Extrinsic

• IX: Intrinsic

• X, II: Common

🧠 7 outside, 9 inside, 10 + 2 together.

Warfarin (Coumadin) — Delayed onset

• Full warfarin effect = 5–7 days.

• Why? Already-existing functional clotting factors must disappear.

Warfarin (Coumadin) — Initial hypercoagulability:

Warfarin starts

→ Protein C decreases early

→ Procoagulant factors remain longer

→ Temporary ↑ clotting

→ Skin necrosis risk.

🧠 Protein C disappears early → Clots can form.

Warfarin (Coumadin) — Bridging

define

Bridging = immediate anticoagulation while warfarin becomes therapeutic.

Warfarin (Coumadin) — Bridging

drugs

UFH/LMWH = works immediately + Warfarin = works fully after several days

• Unfractionated heparin (UFH)

• Low-molecular-weight heparin (LMWH)

→ Overlap approximately 5–7 days until therapeutic INR.

Warfarin (Coumadin) — Bridging

why?

• Why? Protects against clotting during the delayed onset and initial hypercoagulable period in acute thrombosis.

• 🧠 Heparin holds the fort while warfarin wakes up.

⭐ Professor's pharmacist scenario: Patient starts warfarin for acute thrombosis without bridging → recognize the potential risk of…

initial hypercoagulability and skin necrosis.

INR

INR = International Normalized Ratio, standardized from PT (time to clot in sec)

INR monitoring

NR	Meaning
Below 2	↑ Clot risk (usual target)
2–3	Goal for most patients
2.5–3.5	Goal for mechanical valves
Above target	↑ Bleeding risk

INR monitoring

patterns

INR ↑ → anticoagulation ↑ → bleeding risk ↑

INR ↓ → anticoagulation ↓ → clot risk ↑

🧠 HIGH INR = HIGH bleeding risk.

Warfarin toxicities

Memory	Toxicity	Why?
B	Bleeding	Excess anticoagulation
S	Skin necrosis	Protein C depletion
T	Teratogenicity	Fetal hemorrhage/bone abnormalities

• Pregnancy: Professor emphasized avoiding warfarin due to fetal harm.

• 
  

Interactions

Interaction	Effect
CYP inhibitors	↑ Warfarin → ↑ INR
CYP inducers	↓ Warfarin → ↓ INR
Aspirin	↑ Bleeding risk
Liver disease	↑ Bleeding risk
Hyperthyroidism	↑ Warfarin effect
Hypothyroidism	↓ Warfarin effect
Vitamin K	↓ Warfarin effect → ↓ INR

🧠 Inhibitors INcrease INR. Inducers decrease INR.

• 🛑 CYP INhibitors = Workers STOP! → Warfarin builds up ↑ → INR ↑ → 🩸 BLEED

• 🏃 CYP INducers = Workers work FASTER! → Warfarin decreases ↓ → INR ↓ → 🧱 CLOT

Warfarin reversal

Vitamin K + PCC

• Vitamin K1: makes factors functional.

• PCC (Prothrombin complex concentrate): provides factors now.

Situation	Management
Excess INR without bleeding	Hold warfarin + monitor INR
Serious bleeding	Vitamin K1 + rapid clotting-factor replacement

Warfarin - Clinical indications

AVM

• A — AFib: Prevent heart clots → ischemic stroke prevention.

• V — VTE (DVT/PE): Treat/prevent venous clots.

• M — Mechanical valves: Prevent clot formation.

Patient counseling

KIMB

• K — Keep vitamin K intake consistent.

• I — Interactions: Check medications.

• M — Monitor INR regularly.

• B — Bleeding: Report abnormal bleeding.

Patient counseling - example

• Professor's broccoli example:

  • Do not completely avoid vitamin K foods — keep intake consistent.

    • ↑ Vitamin K foods → ↓ INR → ↑ clot risk.

    • ↓ Vitamin K foods → ↑ INR → ↑ bleeding risk.

Warfarin pharmacokinetics

Property	Remember
Absorption	~100% oral bioavailability
Distribution	>99% albumin-bound, small Vd
Metabolism	Liver: CYP2C9, CYP3A4
Half-life	Long → prolonged effects.
Excretion	Urine as inactive metabolites

• Albumin binding + CYP metabolism → drug interactions

Genetics

CYP2C9 (Controls how quickly warfarin is removed)/VKORC1(The enzyme warfarin attacks) variation can cause:

• Increased sensitivity = Lower warfarin dose may be needed.

• Warfarin resistance = Higher dose may be needed.