Drugs Affecting Coagulation

Includes the coagulation cascade and the process of coagulation.
classification and brief details about the drugs affecting the coagulation.

1. Drugs
Affecting
Coagulation
By
Dr. Dinesh Kumar G
Pharm. D

2. ANTICOAGULANTS
I. Used in vivo
A. Parenteral anticoagulants
(i) Indirect thrombin inhibitors: Heparin, Low molecular weight heparins,
Fondaparinux, Danaparoid
(ii) Direct thrombin inhibitors: Lepirudin, Bivalirudin, Argatroban
B. Oral anticoagulants
(i) Coumarinderivatives: Bishydroxycoumarin(dicumarol), Warfarin sod,
Acenocoumarol(Nicoumalone), Ethylbiscoumacetate
(ii) Indandionederivative: Phenindione.
(iii) Direct factor Xainhibitors: Rivaroxaban
(iv) Oral direct thrombin inhibitor: Dabigatran, etexilate

3. II. Used in vitro
A. Heparin:
150 U to prevent clotting of 100 ml blood.
B. Calcium complexing agents:
Sodium citrate: 1.65 g for 350 ml of blood; used to keep blood in the fluid
state for transfusion;
ANTICOAGULANT ACID CITRATE DEXTROSE SOLUTION 2.2 g/100
ml (75 ml is used for 1 unit of blood).
Sodium oxalate: 10 mg for 1 ml blood
Sodium edetate: 2 mg for 1 ml blood

4. Heparin
Heparin is a non-uniform mixture of straight chain mucopolysaccharides with
MW 10,000 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.

5. Mechanism of action
•Anti thrombin III is a peptide
synthesized in the liver and
circulates in the plasma.
•Clotting time is prolonged.
Anticoagulant effect
Prevents conversion of fibrinogen to fibrin
Degrades thrombin, coagulation factors (Xa, IXa)
Binds and activates plasma antithrombin III
Heparin

6. PHARMACOKINETICS
Heparinisalarge,highlyionizedmolecule;not
absorbedorally.
Injectedi.v.itactsinstantaneously,butafters.c.
injectionanticoagulanteffectdevelopsafter60
mins.
Bioavailabilityofs.c.heparinisinconsistent.
Heparindoesnotcrossblood-brainbarrieror
placenta(choiceduringpregnancy).
Itismetabolizedinliverbyheparinaseand
fragmentsareexcretedinurine.

7. Dosage
Heparin is conventionally given i.v.in a bolus dose of 5,000–10,000 U(children
50–100 U/kg), followed by continuous infusion of 750–1000 U/hr. Intermittent
i.v.bolus doses of UFH are no longer recommended.
The rate of infusion is controlled by aPTTmeasurement which is kept at 50–80
sec. or 1.5–2.5 times the patient’s pretreatment value. If this test is not available,
whole blood clotting time should be measured and kept at ~2 times the normal
value.
Deep s.c.injection of 10,000–20,000 Uevery 8–12 hrscan be given if i.v.
infusion is not possible. Needle used should be fine and trauma should be
minimum to avoid hematoma formation. Hematomas are more common with
i.m.injection—this route should not be used.

8. Dosage
Low dose (s.c.) regimen5000 U is injected s.c.every 8–12 hours, started before
surgery and continued for 7–10 days or till the patient starts moving about.
This regimen has been found to prevent postoperative deep vein thrombosis
without increasing surgical bleeding.
It also does not prolong aPTTor clotting time. However, it should not be used in
case of neurosurgery or when spinal anesthesia is to be given.
The patients should not be receiving aspirin or oral anticoagulants. It is
ineffective in high-risk situations, e.g., hip joint or pelvic surgery.

9. Warfarin
Prevents coagulation
Coagulation factors deficiency
Incomplete coagulation factor molecules
formed
Blocks carboxylation of glutamate residues in
factors II, VII, IX, X
Warfarin
•Only in vivo, not in vitro.
•Act indirectly by interfering with the
synthesis of vit K dependent clotting
factors in liver.
•Competitive antagonists of vit K and lower
the plasma levels of functional clotting
factors in a dose-dependent manner.
•Inhibit the enzyme vit K epoxide
reductase (VKOR) and interfere with
regeneration of the active hydroquinone
form of vit K which acts as a cofactor for
the enzyme γ-glutamyl carboxylase that
carries out the final step of γ carboxylating
glutamate residues of prothrombin and
factors VII, IX and X.
Dose (mg): 5 –10

10. •FactorVIIhastheshortestplasmat½
(6hr),itslevelfallsfirstwhenwarfarin
isgiven,followedbyfactorIX(t½24
hr),factorX(t½40hr)and
prothrombin(t½60hr).
•Clottingfactorsdiminisheswithin2–4
hoursofwarfarinadministration,
anticoagulanteffectdevelopsgradually
overthenext1–3daysasthelevelsof
theclottingfactorsalreadypresentin
plasmadeclineprogressively.Thus,
thereisalwaysadelaybetween
administrationofthesedrugsandthe
anticoagulanteffect.Largerinitial
doseshastentheeffectonlyslightly.
Therapeuticeffectoccurswhen
synthesisofclottingfactorsisreduced
by40–50%.

11. Drug interactions
Reduced anticoagulant action
1. Barbiturates (but not benzodiazepines), carbamazepine, rifampin
and griseofulvin induce the metabolism of oral anticoagulants. The
dose of anticoagulant determined during therapy with these drugs
would be higher: if the same is continued after withdrawing the
inducer—marked hypoprothrombinemia can occur—fatal bleeding is
on record.
2. Oral contraceptives: increase blood levels of clotting factors.

12. Drug interactions
Enhanced anticoagulant action
1. Broad-spectrum antibiotics: inhibit gut flora and reduce vit K production.
2. Newer cephalosporins(ceftriaxone, cefoperazone) cause
hypoprothrombinemia by the same mechanism as warfarin —additive action.
3. Aspirin: inhibits platelet aggregation and causes g.i.bleeding—this may
be hazardous in anticoagulated patients. High doses of salicylates have
synergistic hypoprothrombinemia action and also displace warfarin from
protein binding site.
4. Long-acting sulfonamides, phenytoin and probenecid: displace warfarin
from plasma protein binding.
5. Chloramphenicol, erythromycin, celecoxib, cimetidine, allopurinol,
amiodarone and metronidazole: inhibit warfarin metabolism.

13. USES OF ANTICOAGULANTS
•Deep vein thrombosis (DVT) and pulmonary embolism (PE)
•Myocardial infarction (MI)
•Unstable angina
•Rheumatic heart disease; Atrial fibrillation (AF)
•Cerebrovascular disease
•Vascular surgery, prosthetic heart valves, retinal vessel thrombosis,
extracorporeal circulation, haemodialysis
•Defibrination syndrome

14. ANTICOAGULANTS: HEPARINS
DRUG NAME
Unfractionated heparin;
Low molecular weight heparin (LMWH): enoxaparin, dalteparin, tinzaparin
MECHANISM OF ACTION
Enhance the activity of antithrombin III → inhibit Factor Xaand Factor IIa(thrombin) → stop
coagulation cascade
INDICATIONS
•Deep vein thrombosis, pulmonary embolism
•Ischemic stroke, transient ischemic attack
•Coronary artery disease
•Cardiac valve replacement or coronary angioplasty
•Dialysis and Surgical procedures: cardiopulmonary bypass, ECMO, PCI
ROA Unfractionated heparin: IV, SubQ-LMWH: SubQ
SIDE EFFECTS
•Undue bleeding and Injection site reactions
•Hyperkalemia
•Heparin-induced thrombocytopenia (HIT)
•Osteoporosis
CONTRAINDICATIONS
AND CAUTIONS
•Active internal bleeding
•Trauma in the past three months
•History of intracranial hemorrhage or ischemic stroke or HIT
•Gastrointestinal ulcers
•Coagulopathies, bleeding disorders and Thrombocytopenia
•Antiplatelet and thrombolytic medications (increased risk of bleeding)
•Hepatic or renal disease
•Alcohol use

15. ANTICOAGULANTS: HEPARINS
ASSESSMENT AND
MONITORING
•Unfractionated heparin, LMWH
Weight, Vital signs, Laboratory test results; CBC, PTT, aPTT, renal function tests
Administration -Confirm prescribed dose per kg
•Double check prescribed dose with a second nurse
•Have protamine sulfate readily available
•Unfractionated heparin SubQ
•Inject 2 inches or 5 centimeters away from client’s navel
•Pinch the skin slightly
•Insert the needle at a 90 degree angle
•Inject slowly
•Withdraw needle; lightly press the site with dry gauze or an alcohol swab -do not massage the
injection site
•Monitor for signs / symptoms of bleeding; clot formation; aPTT; platelets
CLIENT
EDUCATION
Report
Signs of bleeding; e.g., oozing from the IV insertion site, nosebleed, sudden headache
Signs of clot formation; e.g., new pain, swelling, or warmth in their leg; shortness of breath; sudden
onset of confusion, vision changes, trouble speaking, or one-sided weakness
LMWH (e.g., enoxaparin) self-administration
Review appropriate technique for subcutaneous injections using prefilled syringe
Inject the medication once per day, at the same time each day
May feel minor discomfort or slight bruising may occur at the injection site
Contact healthcare provider for signs of minor bleeding; e.g., bleeding gums, nosebleeds, longer than
normal menstrual periods

16. ANTICOAGULANTS -WARFARIN
CLASS Vitamin K antagonist
MECHANISM OF
ACTION
•Blocks vitamin K epoxide reductase and prevent regeneration of vitamin K epoxide, which is a
cofactor for the enzyme gamma-glutamyl carboxylase, which converts the non-functional forms
of coagulation factors II, VII, IX, and X and anticoagulation proteins C and S, into their
functional forms
•Inhibits maturation of clotting factors II, VII, IX, X and anti-coagulation proteins C, S
•Causes an initial period of hypercoagulation (due to protein C depletion) followed by
anticoagulation
INDICATIONS
•Deep vein thrombosis, pulmonary embolism
•Ischemic stroke, transient ischemic attack, Coronary artery disease
•Cardiac valve replacement or coronary angioplasty
•Coagulation disorders like antiphospholipid syndrome and DIC
•Dialysis and Surgical procedures: cardiopulmonary bypass, ECMO, PCI
ROA PO
SIDE EFFECTS
•Undue bleeding (antidote: Vitamin K1, called phytonadione)
•Hair loss, Fever, Bone marrow depression
•Gastrointestinal effects (anorexia, vomiting, diarrhea, abdominal cramps)
•Warfarin-induced skin necrosis, purple toe syndrome
•Teratogenic
CONTRAINDICATIONS
AND CAUTIONS
•Active internal bleeding, recent trauma in the past three months, history of intracranial
hemorrhage or ischemic stroke, gastrointestinal ulcers, coagulopathies or bleeding disorders
•Surgery of the eye, brain, or spinal cord
•Spinal anesthesia or spinal puncture, Pregnancy and breastfeeding

17. ASSESSMENT AND
MONITORING
Vital signs, signs of bleeding and Laboratory test results: CBC, PT, INR, renal and
hepatic function; negative pregnancy test for female clients of childbearing age
CLIENT EDUCATION
•Purpose of medication: prevent clots, thromboembolism
•Take exactly as directed
•Contact the healthcare provider for a missed dose
•Need for regular INR testing
•Main side effect: bleeding
•Bleeding precautions
•Treatment for minor bleeding
•Cuts: hold gauze or clean cloth over the affected area for 15 minutes
•Nosebleed: tilt their head slightly forward; apply pressure above their
nostrils for 15 minutes
•Immediately notifytheir healthcare provider if injured, hit their head;
experience bleeding longer than 15 minutes; notice blood in their vomit,
stool, or urine; new onset of chest or back pain, shortness of breath,
weakness, dizziness, or confusion
•Dietary modifications and avoid large day-to-day variations in the amount
of vitamin K
•Avoid alcohol, nicotine products
•Consult with healthcare provider before taking over the counter
medications or supplements

18. Thank You