Pharmacology of drugs acting on blood and

blood forming organs

Dr Urmila M. Aswar,

Sinhgad Institute of Pharmacy, Narhe, Pune -41

Hemostasis: is a process which causesbleeding to stop, meaning to keep bloodwithin a damaged blood vessel (theopposite of hemostasis is hemorrhage)

Clotting disorders is a term used todescribe a group of conditions in whichthere is an increased tendency, oftenrepeated and over an extended period oftime, for excessive clotting.

Thrombophilia known as

hypercoagibility. It affects a large number

of people around the world. It affects

approximately 5% to 7% of the European

population.

Blood coagulation

Intrinsic pathway : all factors needed for

Blood coagulation are in plasma. Slow

process as lot many factors are needed to

be activated.

Extrinsic pathway: also needs tissue

factor-thromboplastin. Occurs with in

seconds.

Factors opposing coagulation

Antithrombin protein C,

Antithromboplastin

fibrinolysin

Thrombosis

Can be in artery or vein.

Symptoms depend on

Where it has formed

Area

Is it a emboli

There are different terms used to further define these thrombotic episodes, such as deep vein thrombosis (DVT) or peripheral vascular disease, when the clots are in the arterial system (usually in the extremities).

Triggering factors

Women are more sensitive

Pregnancy, oral contraceptives and post-

menopausal hormone replacement

therapy are all triggering events for DVT

in women with thrombophilia.

Factor V Leiden: hypercoagulation

factor V Leiden

Discovered in Leiden city of Neitherland

Factor V is responsible for activation of

factor X and XII which further stimulates

thrombin formation.

There is mutation in the gene responsible.

So that PK C couldn’t degrade factor V. so

it is over activity of factorV.

Anticoagulants

Used in vitro

Heparin

Ca complexing agents

Used in vivo

Heparin: LMW heparin

Oral anticoagulants: 1. Coumarin

derivatives

2. Indandione derivatives: Phenindione

Heparin

Isolated from liver

MW 10,000-20,000

Mucopolysacchride

chain

Contains negative

charge

Present in mast cells

Present in lung, liver

and intestine

Glycosaminoglycans

Actions

Activating antithrombin III

Binds to intrinsic clotting factors: Xa, IIa,

IXa, XIa, XIIa, XIIIa and blocks their

activity.

No effect onVIIa of extrinsic pathway.

It inhibits conversion prothrombin to

thrombin by Xa.

Also it inhibits conversion of fibrinogen to

fibrin, Inactivates IIa.

Low concentration interfere with intrinsic

pathway.

High affect both.

It inhibits platelet aggregation

It releases lipoprotein lipase from liver

and clears VLDL, chylomicrons and

triglycerides from plasma.

Kinetics

As it large inonized molecule, Not Absorbed orally

Does not cross BBB or placenta

T1/2: 1 hr

Units: 1U : the amt of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hr after addition of 1% CaCl2 solution

Heparin sod: 1 mg has 120-140U of activity

Dosage

Given IV 5,000-10,000U adults every 4-6

hrs

Infusion given (750-1000U) till bleeding

incidence happen.

Children: 50-100 U/kg

Adverse effects

Bleeding

Thrombocytopenia

Alopecia (transient)

Osteoporosis

Hypersensitivity reactions: urticaria, fever,

anaphyllaxis

Contradications

Bleeding disorders

Severe hypertension

Ocular and neurosurgery

Chronic alcoholics

Aspirin and other antiplatelet drugs

Low-molecular-weight heparins

(LMWHs) LMWHs, in contrast, consist of only short

chains of polysaccharide. LMWHs are

defined as heparin salts having an average

molecular weight of less than 8000 Da.

These are obtained by various methods of

fractionation or depolymerisation of

polymeric heparin.

LMWHs have a potency for factor Xaactivity and for anti-thrombin activity (ATIII).

More specific in action

Less effects on platelets

Less hemorrhagic complications.

Good p’kinetic profile

BA improves.

Longer T1/2

Dose is given in mg and not in unit

LAB MONITORING NOT NEEDED.

Uses

Pulmonary embolism

Deep vein thrombosis

Surgeries

Eg Nadoparin, Enoxaparin, Dalteparin,

Raviparin etc.

Fondaparinux

It is a synthetic pentasacchride. It is an antithrombin III mediated selective inhibition of factor Xa. Which further inhibits thrombin formation.

Administered s.c daily.

Dose: 2.5 mg

BA: 100%

T1/2: 17-21 hrs

Excreted unchanged in urine

Lesser antiplatlet action chances of thrombocytopenia is less.

Oral anticoagulants

Bishydroxycoumarin was made in 1941

Warfarin was used as anti-cogulant In vivo only.

They act by interfering with synthesis of vit Kdependent clotting factors.

They behave as competitive inhibitors of vit K.They interfere with regeneration of active form ofvitamin K, which is essential for carboxylation ofclotting factors-VII, IX, X.

Vitamin K is involved in the carboxylation ofcertain glutamate residues in proteins to formgamma-carboxyglutamate residues.

Caroboxylation enhances binding of clottingfactors to Ca2+ leading to coagulation.

Reduced Vitamin K Oxidised Vitamin K

Warfarin

NADNADH

Descarboxy factor: VII,IX,X Carboxylated factor: VII,IX,X

Synthesis of clotting factors diminishes within 2-4hrs of warferin administration the anticoagulanteffects develops gradually over next 1-3 days.

Therapeutic effect occurs when synthesis ofclotting factors is reduced by 40-50%.

Pharmacokinetics: Racemic warferin sodium:the most popular oral anticoagulant.

R+S, S is more potent, metabolized by oxidation.

Completely absorbed from stomach.

99% is plasma bound.

It crosses placenta and secreted in milk.

Bishydroxycoumarin (Dicoumarol)

Absorbed orally

Metabolism is dose dependent

T1/2 is prolonged at higher doses

Has poor GI tolerance

Available as 50 mg tab

Acenocoumarol

T1/2 of 8 hrs. produces an active

metabolite.

T1/2: 24 hrs.

Acts rapidly

Adverse effects

Bleeding

Epistaxis

Hematuria

Bleeding in GIT

Internal hemorrhage

Treatment:

Stop anticoagulant

Blood transfusion

Plasma replenishment

Vit K1 administration

Factors enhancing effect of oral

anticoagulants Malnutrition

Prolonged antibiotic use

Liver disease : low synthesis of CF

Newborns: low CF

Hyperthyroidism: Fast degradation of CF

Factors decreasing the effect of oral

anticogulants Pregnancy

Nephrotic syndrome: drug bound to

plasma protein is lost in urine.

Contraindications

Pregnancy: skeletal abnormalities, foetal

warfarin syndrome– hypoplasia of nose,

eye socket, hand bones and growth

retardation.

If given in later stage of pregnancy, it can

cause CNS defects, foetal death.

Drug interactions

Enhanced anticoagulant action

1. Braod spectrum antibiotics

2. Newer cephalosporins eg moxalactam, cefamandole, produces hypoprothrombinemia by the same mech. as warfarin.

3. Aspirin: inhibits platelet aggregation, also displaces warfarin from PBS.

4. Phenylbutazone: Decreases PB of warfarin

5. Long acting sulfonamides, indomethacin, phenytoin, probenicids: competitor for protein binding

6. Chloramphinicol, erthromycin, cimetidine, allopurinol, amidarone, metronidazole: inhibits warferin metabolism

7. Tolbutamide and phenytoin: inhibits warferin metabolism

8. Phenformin, anabolic steroids, quinidine, clofiberate, potentiate warferin action

9. Liq paraffin: reduces vit K absorption.

Reduced anticoagulant action

1. Barbiturates and other hypnotics (not

BZD), rifampin, grisofulvin induce

metabolism of oral anticoagulant

2. Oral contraceptives increases level of

clotting factors.

Uses

Deep vein thrombosis and pulmonary embolism: venous thrombi are fibrin thrombi- 3 month therapy

Post stroke required prophyllaxis.

Myocardial infarction: arterial thrombi are platelet thrombi. Not very beneficial. Aspirin+heparin followed by warfarin.

Rheumatic heart disease, auricular flutter: Warfarin/ low dose heparin/ low does aspirin

Cerebrovascular disease: little value

Preferred in ischaemic attacks due to

emboli.

Vascular surgery, prosthetic heart valves,

retinal vessel thrombosis: anticoagulants

are given along with antiplatelet drugs for

prevention of thromboembolism.

Fibrinolytics

These drugs are used to lyse the clot.

Curative

Fibrin is formed

Fibrinolytic system get activated

t-PA activates Plasminogen---Plasmin is

the serine protease which digest fibrin

Plasminogen is present in bound (fibrin)

and free form.

Fibrinolysis

Fibrinolytics

Strptokinase

Urokinase

Altelase

Streptokinase

Obtained from Streptococci C

Activates plasminogen

T1/2: 30-80 m

Antigenic

less expensive

Urokinase

Isolated from human urine

Prepared from human kidney cells

Activates plasminogen directly

T1/2: 10-15 m

Side effects: Less allergic

fever

Alteplase

Produced by recombinant DNA tech.

Activates plasminogen bound to fibrin.

T1/2: 4-8 m

Expensive

Uses

Acute MI

Therapy to be initiated 12 h of symptoms

Can be given IV

Heparin or aspirin is started thereoff

Deep vein thrombosis

Pulmonary embolism

Peripheral arterial occlusion

To be treated with in 72 hrs advised if throbectomy is not possible

Antiplatelet drugs

COX inhibitor: Aspirin

Aspirin is indicated as prophylaxis against

transient ischemic attacks, myocardial

infarction and thromboembolic disorders.

It is also used for the treatment of acute

coronary syndromes and in the

prevention of reoclusion in coronary

revascularization procedures.

Dose: 75 mg to 325 mg

Ticlopidine is the oldest thienopyridine

currently available. It is approved for

secondary prevention of thrombotic

strokes in patients intolerant of aspirin

and for prevention of stent thrombosis in

combination with aspirin.

Clopidogrel is approved for prevention

of atherosclerotic events following recent

myocardial infarction, stroke or

established peripheral arterial disease. It

has a better safety profile than ticlopidine.

Phosphodiesterase inhibitors

Dipyridamole acts as vasodilator and

antiplatelet agent. It blocks

phosphodiesterase in platelet leading to

increase in cAMP in platelet. Adenosine

decreases platelet aggregability.

It is used in combination with aspirin or

warfarin in the prophylaxis of

thromboembolic disorders.

GPIIb/IIIa inhibitors

Platelet membrane GPIIb-IIIa receptors

constitute the final common pathway of

platelet aggregation, the integrin

GPIIb/IIIa antagonists prevent cross-

linking of platelets.

Abciximab is a human-murine monoclonal

antibody directed against GPIIb/IIIa,

UESES

CAD: MI

Coronary bypass implant

Prosthetic heart valves

Venous thrombosis

Peripheral vascular disease