Lec.9 PHARMACOLOGY College of DentistryDr. Zainab Ghalib Al-Jassim Baghdad University

DRUGS USED IN DISORDERS OF COAGULATION

Hemostasis refers to the finely regulated dynamic process of maintaining

fluidity of the blood, repairing vascular injury, and limiting blood loss

while avoiding vessel occlusion (thrombosis) and inadequate perfusion of

vital organs.

Either excessive bleeding or thrombosis represents a breakdown of the

hemostatic mechanism. Common causes of dysregulated hemostasis

include hereditary or acquired defects in the clotting mechanism and

secondary effects of infection or cancer.

MECHANISMS OF BLOOD COAGULATION

Coagulation (also known as clotting) is the process by

which blood changes from a liquid to a gel, forming a clot. This leads to

cessation of blood loss from a damaged vessel followed by repair.

The mechanism of coagulation involves activation, adhesion, and

aggregation of platelets along with deposition and maturation of fibrin.

Disorders of coagulation are disease states which can result in bleeding

(hemorrhage or bruising) or obstructive clotting (thrombosis).

Coagulation involves both a cellular (platelet) and a protein (coagulation

factor) component. Coagulation begins almost instantly after an injury to

the blood vessel has damaged the endothelium lining the vessel. Exposure

of blood to the space under the endothelium initiates two processes:

changes in platelets, and the exposure of subendothelial tissue factor to

1

plasma Factor VII, which ultimately leads

to fibrin formation. Platelets immediately form a plug at the site of

injury; this is called primary hemostasis. Secondary hemostasis occurs

simultaneously: Additional coagulation factors or clotting factors beyond

Factor VII respond in a complex cascade to form fibrin strands, which

strengthen the platelet plug.

2

THROMBUS VERSUS EMBOLUS

It is important to distinguish between thrombi and emboli: A clot that

adheres to a vessel wall is called a “thrombus,” whereas an intravascular

clot that floats in the blood is termed an “embolus”. Thus, a detached

thrombus becomes an embolus. Both thrombi and emboli are dangerous,

because they may occlude blood vessels and deprive tissues of oxygen

and nutrients.

PLATELET INHIBITORS (Antiplatelet)

3

Abciximab

Aspirin

Cilostazol

Clopidogrel (PLAVIX)

Dipyridamole

Eptifibatide

Prasugrel

Ticlopidine

Tirofiban

→ are agents that decrease platelet aggregation and inhibit thrombus

formation.

ASPIRINAspirin, also known as acetylsalicylic acid (ASA) is part of a group of

medications called nonsteroidal anti-inflammatory drugs (NSAIDs), but

differs from most other NSAIDs in the mechanism of action. Aspirin has

similar effects (antipyretic, anti-inflammatory, analgesic) to the other

NSAIDs but has also antiplatelet action.

Mechanism of action:

Irreversibly inhibits cyclooxygenase (COX) enzymes, both COX-1 and

COX-2 (enzymes responsible for formation of prostanoids,

including prostaglandins and thromboxane), inhibition of COX can

provide relief from the symptoms of inflammation and pain.

It has→

Antipyretic, anti-inflammatory action →because it interferes with

PGE2 (prostaglandin E2) synthesis.

4

Antiplatelet action→ because it ↓ platelet production of TXA2

(thromboxane A2) (platelet activator and vasoconstrictor).

Uses

Antipyretic, anti-inflammatory, analgesic.

Prophylaxis and treatment of arterial thrombosis

Side effects

Gastritis and GI bleeding because of decreased synthesis of

gastroprotective prostaglandins.

↓ GFR(glomerular filtration rate) because of decreased renal

vasodilatory prostaglandins

Can precipitate asthma, because inhibition of COX may favor

production leukotrienes.

Chronic mild intoxication (Salicylism) causes tinnitus, ↓ hearing,

and vertigo.

Acute intoxication leads to metabolic acidosis (accumulation of

acid), respiratory alkalosis (↑respiratory rate), hyperpyrexia, coma,

and cardiopulmonary collapse.

Contraindication

Peptic ulcer disease

Avoid in children because of the potential for Reye's syndrome

(fatal syndrome causes mainly fatty liver with minimal

inflammation and cerebral edema (swelling of the brain))

Metabolism

• Low doses for cardioprotection (75-100 mg),

• higher doses for inflammation( 300 mg),

5

• COX inhibition is irreversible, but 10% of platelets replaced each

day; therefore, antiplatelet effect lasts for about 7 days.

☺☻Note: Prostaglandins have been found in almost every tissue in human.

Prostaglandins have two derivatives:  prostacyclins and thromboxanes. Prostacyclins

are powerful locally acting vasodilators and inhibit the aggregation of blood platelets.

Through their role in vasodilation, prostacyclins are also involved in inflammation.

They are synthesized in the walls of blood vessels and serve the physiological

function of preventing needless clot formation, as well as regulating the contraction

of smooth muscle tissue. Conversely, thromboxanes (produced by platelet cells)

are vasoconstrictors and facilitate platelet aggregation. Their name comes from their

role in clot formation (thrombosis).

CLOPIDOGRIL

Mechanism

Irreversibly inhibits the platelet ADP receptor, blocking ADP-mediated

platelet activation.

Uses

Prophylaxis and treatment of thrombosis.

Usually given in combination with aspirin; because of their

complementary mechanisms of action.

Side effects

Bleeding

ANTICOAGULANTSArgatroban

6

Dabigatran

Dalteparin

Enoxaparin

Fondaparinux

Heparin

Lepirudin

Tinzaparin

Warfarin

→ substances that prevent or reduce coagulation of blood, prolonging the

clotting time.

HEPARIN

Mechanism

A fast acting anticoagulant, with a high binding affinity for antithrombin

III (AT III) (that binds and inactivate thrombin and other factors like the

factors X, IX, and XI).

Uses

Prophylaxis and treatment of thrombosis.

Side effects

Bleeding

Thrombocytopenia

WARFARINMechanism

7

Oral anticoagulant that interferes with synthesis of vitamin-K dependent

clotting factors in the liver such as factors II, VII, IX and X.

Uses

Prophylaxis and treatment of thromboembolism.

Side effects

Bleeding

THROMBOLYTIC AGENTSAlteplase

Reteplase

Streptokinase

Urokinase

→ drugs that dissolve blood clots.

Mechanism

Fibrinolytics that directly convert inactive plasminogen into the

proteolytic enzyme plasmin. Plasmin then cleaves fibrin clots.

Uses

Pulmonary emboli, DVT (deep vein thrombosis), arterial thrombosis,

acute non-hemorrhagic CVA (Cerebrovascular accident/ stroke) and in

acute ST-elevation MI.

8

Given by IV route.

TREATMENT OF BLEEDING

Aminocaproic acid

Aprotinin

Protamine sulfate

Tranexamic acid

Vitamin K1 (phytonadione)

→These drugs reduce bleeding in patients with hemophilia and other

hemorrhagic conditions.

Aminocaproic acid and Tranexamic acid works as antifibrinolytic.

They bind reversibly to plasminogen and block its activation to plasmin.

With NO activation of plasmin, there is a reduction in fibrinolysis. This

consequently will reduce the amount of bleeding post-

surgery. Tranexamic acid has roughly eight times

the antifibrinolytic activity of an older analogue, aminocaproic acid.

Tranexamic acid is used in dentistry in the form of a 5% mouth rinse after

extractions or surgery in patients with prolonged bleeding time; e.g., from

acquired or inherited disorders.

TREATMENT OF ANEMIA

Cyanocobalamin (B12)

Erythropoietin

Folic acid

Iron

9

→They help to produce healthy red blood cells and prevent anemia.

TREATMENT OF SICKLE CELL ANEMIAHydroxyurea (increases the concentration of  hemoglobin)

Pentoxifylline (improves red blood cell deformability/ anti-inflammatory

action)

MANAGEMENT OF HYPERLIPIDEMIA

Hyperlipidemia is an increase in the lipids, which are a group of fats or

fat like substances in the blood. Cholesterol and the triglycerides are the

two lipids in the blood. Elevation of one or both of these lipids is seen in

hyperlipidemia.

Serum cholesterol levels above 240 mg/dL and triglyceride levels above

150 mg/dL are associated with atherosclerosis.

Atherosclerosis is a disorder in which lipid deposits accumulate on the

lining of the blood vessels, eventually producing degenerative changes

and obstruction of blood flow. Atherosclerosis is considered to be a major

contributor in the development of heart disease.

Triglycerides and cholesterides are insoluble in water and must be bound

to a lipid-containing protein (lipoprotein) for transportation throughout

the body.

10

Several lipoproteins are found in the blood mainly the low-density

lipoproteins (LDL), the high density lipoproteins (HDL).

Low-density lipoproteins (LDL) transport cholesterol to the peripheral

cells. When the cells have all of the cholesterol they need, the excess

cholesterol is discarded into the blood. This can result in an excess of

cholesterol, which can penetrate the walls of the arteries, resulting in

atherosclerotic plaque formation. Elevation of the LDL increases the risk

for heart disease.

High-density lipoproteins (HDL) take cholesterol from the peripheral

cells and bring it to the liver, where it is metabolized and excreted.The

higher the HDL, the lower the risk for development of atherosclerosis.

Therefore, it is desirable to see an increase in the HDL (the “good”

lipoprotein) because of the protective nature of its properties against the

development of atherosclerosis and a decrease in the LDL.

DiagnosisA laboratory examination of blood lipids, called a lipoprotein profile,

provides valuable information on the important cholesterol levels, such

as:

• Total cholesterol

• LDL (the harmful lipoprotein)

• HDL (the protective lipoprotein)

• Triglycerides

Risk factors in the development of atherosclerotic heart disease are:

Hyperlipidemia, particularly elevated serum cholesterol and LDL

levels.

Family history

11

Cigarette smoking

High blood pressure

Age (men older than 45 years and women older than 55 years)

Low HDL levels

Obesity

Diabetes

MANAGEMENT OF HYPERLIPIDEMIA

The various types of drugs used to treat hyperlipidemia are:

1-HMG-CoA reductase inhibitors (STATINS)

2-Fibric acid derivatives (FIBRATES)

3-Niacin

4-Bile acid sequestrants (RESINS)

5-Cholesterol absorption inhibitors

1- HMG-CoA Reductase Inhibitors (Statins)

Fluvastatin, Lovastatin, Atrovastatin, Simvastatin.

Mechanism:

HMG-CoA (3- hydroxy-3-methyglutaryl coenzyme A) reductase is an

enzyme that is a catalyst in the manufacture of cholesterol. Thus, these

drugs block endogenous cholesterol synthesis. They result in large

12

decrease in the levels of cholesterol, LDL and serum triglycerides and a

small increase in blood levels of HDLs.

Uses: drugs of choice for hypercholesterolemia.

Side effects: The most important adverse side effects are muscle

problems, an increased risk of diabetes mellitus, and increased liver

enzymes in the blood due to liver damage.

2-Fibric Acid Derivatives (Fibrates)

Gemfibrozil, Fenofibrate, Clofibrate

Mechanism:

Gemfibrozil binds to and activates Peroxisome proliferator-activated

receptor alpha (PPAR-alpha), which is a major regulator of lipid

metabolism in the liver. This results in a large decrease in triglycerides

(↓TG) and also increase HDL.

Fenofibrate is similar but causes greater increase in HDL.

Clofibrate is less well tolerated.

Uses: Hypertriglyceridemia.

Side effects: GI distress (nausea, vomiting, abdominal

pain), myopathy (muscle pain), gallstones.

3-Niacin

13

Mechanism: Niacin reduces hepatic synthesis of triglyceride and results

in a large ↓in TG level and medium ↑ HDL and ↓ cholesterol.

Uses: Hypercholesterolemia with concomitant Hypertriglyceridemia

Side effects: Generalized flushing sensation, of warmth, severe itching,

GI distress, ↑liver enzymes, hyperuricemia and Glucose intolerance.

4- Bile Acid Sequestrants (Resins)

Cholestyramine, Colestipol

Mechanism:

These drugs bind to bile acids to form an insoluble substance that cannot

be absorbed by the intestine, so it is secreted in the feces. With increased

loss of bile acids, the liver uses cholesterol to manufacture more bile.

This is followed by a decrease in cholesterol levels.

Uses: 2nd line therapy for hypercholesterolemia.

Side effects: Constipation, bloating, nausea, steatorrhea, and deficiency

of lipid-soluble vitamins (A, D, E, and K).

Note: Bile, which is manufactured and secreted by the liver and stored in

the gallbladder, emulsifies fat and lipids as these products pass through

the intestine. Once emulsified, fats and lipids are readily absorbed in the

intestine.

14

5-Cholesterol Absorption Inhibitors

Ezetimibe

Inhibits intestinal cholesterol absorption → ↓ total cholersterol.

Uses: Hypercholesterolemia. Usually used with statins.

Orlistat (Xenical)

inhibts GIT lipase and interferes with TG digestion to free fatty acids.

Used to treat obesity but not used as a therapy for Hyperlipidemia

15