Agents affecting blood

Dysfunctions of blood
Thrombosis the formation of an
unwanted clot within the blood vessls or
heart
Bleeding disorders due to failure of
hemostasis and include hemophilia and
vitamin K deficiency
Anemia -- caused by nutritional deficiency

Anticoagulants
Antiplatelet drugs antithrombolic drugs
Fibrinolytic drugs
Hemostatics
Agents Used in Anemia
Hematopoietic growth factors
Plasma volume expanders

Clot formation
requires platelet
activation and
aggregation
(white clot or
platelet clot),
followed by
formation of a
fibrin clot (red
clot).

intrinsic pathway

process of normal blood coagulation

extrinsic pathway

a,a

III

Thrombin(a)

Prothrombin()
+

fibrinogen

IIIa

Fibrin
(soluble)

Fibrin clot

Fibrin
( Insoluble)

Coagulation Cascade Animation - Physiology of Hemostasis.mp4

1 anticoagulants
Anticoagulants are drugs employed in
preventing blood coagulation. They
inhibit certain clotting factors in the liver.
The function of them is to:
1) prevent the formation of new blood
clots.
2) keep existing blood clots from growing
larger.

Classification of anticoagulants
Anticoagulants both in vivo and vitro:
e.g. Heparin
Anticoagulants in vivo: dicoumarol
Anticoagulants in vitro: Sodium citrate

1. Heparin
1.1 source and chemistry
(1)large amount of negative charge
(2)strong acidity

1.2 Pharmacological effects

1. Anticoagulative effect
Mechanism: accelerate inactivation of
clotting factors.(a, a, a, a, a )
by enhancing the anticoagulative activity
of AT ( antithrombin ).

III

Thrombin(a)

Prothrombin()
+

fibrinogen

IIIa

Fibrin
soluble

Fibrin clot

Fibrin
insoluble

Mechanism of heparin
This reaction happens
in normal
physiological state, but
its very slow and
weak.
In the presence of
heparin (which acts as
an catalyst), it will be
accelerated by more
than 1,000 times

Characteristics of anticoagulative effect

effective both in vivo and in vitro

quick onset and potent effects
efficacy positively relative to mocular weight

1.2 Pharmacological effects

2.Other effects

adjusting blood lipid

anti-inflammatory effect
anti-proliferative effect on vascular
smooth muscle cell
inhibiting pletelet aggregation
.

1.3 Clinical uses

1) thromboembolic disease:
deep venous thrombosis(DVT),
pulmonary embolism, unstable angina,
acute myocardial infarction, cerebral infarction
2) DIC (Disseminated intravascular coagulation):
early stage
3) extracorporal circulation
(eg. dialysis machine)

1.4 Adverse reactions

Spontaneous hemorrhage :
monitoring of aPTT
antagonist: protamine sulfate(1mg:100u)
Heparin-induced thrombocytopenia:
(a decrease in circulating platelets)
210 days of therapy, 3% ,
Others : allergic reaction
osteoporosis

1.5 Contraindications:
1. Bleeding tendency:
Severe hypertension
Ulcer
surgery of the brain ,eye, spinal cord
2. pregnancy
3. Renal and hepatic dysfunctions

Coumarin derivatives
---Oral anticoagulants
These agents are often referred to
as oral anticoagulants because they are
administered orally, which exists as the
main difference from heparin.

 Warfarin
Dicoumarin
Acenocoumarin

4.1 pharmacological effects

Anticoagulative effect
1)

mechanism:

antagonizing Vit Kinhibiting the

synthesis of cloting factor ,,,

Mechanism of Oral anticoagulants

Several clotting factors
(, , , ) depend on vit K
as a coenzyme in their complete
synthesis by the liver.
Oral anticoagulants antagonize VitK
inhibiting the synthesis of
clotting factor,,,
inhibiting coagulation

2)

characteristics

(1) oral administration

(2) effective in vivo, not in vitro
(3) slow onset, long duration
(4) overcome by administration of
Vitamin K

 4.2 clinical uses:

For long use

Prevent acute deep vein thrombosis

or pulmonary embolism
Prevent venous throboembolism in
patients undergoing orthopedic or
gynecological surgery
Prevent systemic embolization in
patients with myocardial infarction,
prosthetic heart valves or chronic
atrial fibrillation

4.3 adverse effects

4.3.1 Spontaneous hemorrhage :
monitoring of PT

Treatment: withdrawal of

the drug; administration of vitamin K and

fresh blood
4.3.2 others: birth defect (warfarin)
Allergic reaction

 4.4 drug interactions

4.4.1 enzyme inducerbarbiturates
4.4.2 competitive antagonist: Vit K
4.4.3 high PPBR: aspirin, quinidine,
sulfonamide, phenylbutazone
4.4.4 enzyme inhibitor: cimetidine, isoniazid
4.4.5 PLT inhibitors: aspirin

Anticoagulants in vitro

Sodium citrate, potassium oxalate

Mechanism: Ca2+
Uses:
prevent blood coagulation in vitro

2 antiplatelet drugs

Antipletelet drug---- Drug that inhibits

platelets from aggregating to form a plug.
They are used to prevent clotting and
alter the natural course of
atherosclerosis.

Platelets activation
processes involve
three steps:
1.adhesion to the
site of injury
2.release of
intracellular
granules
3.aggregation of
the platelets.

Classification
Inhibitors of platelet metabolism
Agents inhibiting platelet activity
induced by ADP: Ticlopidine
Thrombin inhibitor: argatroban
IV GPb / a receptor blocker:
abciximab

aspirins

TXA2

COX

AA

()

AC

COX

aspirinl

PGI2
()

Dipyridamole

AC

PDE

cAMP

aggregation
(PLT)

AC= Adenylate Cyclase

cAMP

aggregation
(endothelium)

5-AMP

 Inhibitors of platelet metabolism

Cyclooxygenase inhibitors: Aspirin
PDE (Phosphodiesterase) inhibitors :
Dipyridamole
TXA2 synthetase inhibitor: Ridogrel

Activators of adenylate cyclase:

epoprostenol (PGI2)

 Cyclooxygenase inhibitors:
Aspirin
Aspirin is a classic old drug which is used
as a NSAIDs for more than 100 years.
Besides antipyretic, analgesic and antiinflammatory activities, it can inhibit
platelet aggregation.

Pay attention!
at small dose (5075mg/d)
inhibit the synthesis of TXA2
which causes platelet aggregation
at higher doses (> 320 mg/day)
inhibits the synthesis of PGI2
which inhibits platelet aggregation.

Clinical Uses
Prophylaxis after cardiac operation
to reduce the incidence of recurrent
myocardial infarction (MI)
Prophylaxis for transient ischemic attacks
(TIA) or post TIA

 PDE inhibitors : Dipyridamole

Mechanism :
1) PDE cAMP

aggregation

2) the uptake of adenosine AC

Clinical use: Substitute of aspirin
prosthetic heart valves, etc.

 TXA2 synthetase inhibitor:

Ridogrel
More effective than aspirin
Fewer adverse reaction

 Agents inhibting platelet activity

induced by ADP: Ticlopidine
Broad spectrum inhibitor of PLT aggregation
Mechanism: disturb the release of -granule
and binding of fibrin to GP b/ a receptor
induced by ADP
Clinic use: thromboembolic disease
Severe toxicity: nausea, bone marrow
depression

 Thrombin inhibitor:
Argatroban
Thrombin inhibitor
has a short half-life, is given by continuous
intravenous infusion, and monitoring is
done by aPTT.
Its clearance is not affected by renal
disease but is dependent on liver function.

hirudin
irreversible thrombin inhibitor from the
leech
now available in recombinant form as
lepirudinin.
has a short half-life, but it accumulates in
renal insufficiency and no antidote exists.
Mainly used after surgery

IV GPb / a receptor blocker:

abciximab

activation of glycoprotein receptor on PLT

membrane is the final common pathway for
platelet aggregation.
Mechanism: blockade of glycoprotein
receptors on PLT membrane

43 Hemostatics

 Coagulants
Vitamin K
Antifibrinolytic drugs
Tranexamic acid
Aminomethylbenzoic acid
Thrombin
Vasoconstrictors Etamsylate
Posterior pituitary()

 Vitamin K
[Source and types]
Vitamin K is found in meats, dairy
products, leafy green vegetables
Two natural forms : VitK1,VitK2
Two synthesized forms: VitK3,VitK4

Mechanism of vitamin K
Smoe clotting factors
(, , , ) that
are involved in the
coagulation reactions
depend on vitamin K
as a coenzyme in
their complete
synthesis by the liver.

III

Thrombin(a)

Prothrombin()
+

fibrinogen

IIIa

Fibrin
soluble

Fibrin clot

Fibrin
insoluble

 Clinical uses:
Hemorrage resulting from VitK deficiency
1) Excess of oral anticoagulants
2) Obstructive jaundice and biliary fistula
(vitamin K is a fat-soluble vitamin )
3) long term use of broad spectrum antibiotics:
(some vitamin K is synthesized by intestinal
bacteria.)
4) Prevent hemorrhage in newborn baby and
premature infants.

5 Agents Used in Anemia

Anemia ---a deficiency in erythrocytes or
hemoglobin.
Normal value
Adult male
Adult famale

RBC(104/L)
400-550
350-500

Hb(g/dL)
12 -16
11-15

Types of anemia

Iron-deficiency anemia
megaloblastic anemia
aplastic anemia
hemolytic anemia

1. Iron
p.o.: Ferrous sulfate
Ferric ammonium citrate
Ferrous fumarate
i.m.: Iron dextran

Pharmacological actions:
Iron is part of hemoglobin, the oxygencarrying component of the blood. Irondeficient people tire easily because their bodies
are starved for oxygen.
Iron is also part of myoglobin. Myoglobin
helps muscle cells store oxygen.

Clinical uses:

treatment or prevention of iron

deficiency anemia
1) chronic blood loss in heavy
menstrution or hemorrhoid
2) insufficient intake during periods of
accelerated growth in children, or in
pregnant women.
10~14d 4~8w 2~3m

Adverse reactions
1) p.o. : marked gastrointestinal irritation
2) i.m. : remarkable local irritation
3) acute iron toxicity: >1g
gastric irrigationshockdeath
lavage: phosphate or carbonate
deferoxamine: a potent iron chelating
compound

 2. Folic acid
Process in body
FA FH2 FH4 5-CH3-FH4
Machinism: One carbon unit carrier
Reduction of folic acid
dTMP DNAmegaloblastic anemia
amino acid biosynthesis

 Clinical uses:
1. Megaloblastic anemia
2. Pernicious anemia
3. Megaloblastic anemia caused by FH2
reductase
inhibitors: methotrexate,
Pyrimethamine(

3. Vitamin B12
Source:
Meat (especially liver), eggs,
and dairy products.
Pharmacokinetics:
Requirements of Vitamin B12:
1g/d
Storage: in liver

Pharmacological Action:

dUMP

dTMP

1) methyl transfer
pernicious anemia
2) isomerization of
methylmalonyl-CoA to
succinyl-CoA
destroy integrity of myelin
sheath nerve damage
TAC

Clinical uses:
1. Megaloblastic anemia
2 .Pernicious anemia
3 .Nervous system diseases
4. Hepatopathy