4. Drugs acting on blood

5. Cholesterol Absorption Inhibitors, Fish Oils and Orlistat

Cholesterol Absorption Inhibitors


It interferes with absorption of cholesterol and phytosterols in small intestine by interfering with a transport protein NPC1L1.

  • Decreases absorption of cholesterol
  • Decrease delivery of cholesterol to liver
  • In turn, decrease production of lipids
  • Decrease LDL by 17-18%
  • Decrease TG by 6%
  • Increase HDL by 1-2%


Not very potent drug. Given only when patient is not responding to other drugs.


a. Absorption –Exetimibe is readily absorbed

b. Metabolized by glucuronidation

c. PPC achieved in 12 hours

d. Half life –undergoes enterohepatic circulation so half life is increased up to 22 hours.

e. Elimination -80% in faeces

f. When co-administered with fibrates, there is increased plasma concentration of this drug.

g. When co-administered with bile acid binding resins, concentration decreases.


Primary hypercholesterolemia


Adverse effects

1. GIT –can interfere with absorption of lipids -steatorrhea


2. Can produce liver injury

3. Rarely myositis

4. Does not interfere with absorption of fat soluble vitamins

 Fish oils

  • Precursors of TGs
  • Decrease levels of VLDL, TG, and LDL.
  • Dose -5 g/day.


  • Weight reducing agent that decreases plasma lipid levels.
  • Decreases absorption of fatty acids and increases excretion, so plasma levels of lipids are decreased
  • Inhibits lipases in stomach, pancreas and intestines and decreases plasma lipid levels.
  • Loss of dietary lipids is about 30%
  • Loss of weight is about 5-10%

Adverse effects

GIT upsets

Interfere with absorption of fat soluble vitamins

Interfere with absorption of lipids


Given in a dose of 120 mg, thrice a day. Effect is very slow, and takes about 1-2 months. If there is decrease in weight in those 1-2 months, then continued for 2 years.

4. Drugs acting on blood

4. Probucol and Nicotinamides


Butylated hydroxytoluene, not commonly used. It is used only in individuals who do not respond to other drugs.

  • Decrease cholesterol by about 10-15%
  • Decrease LDL by 10%
  • Decrease LDL by increasing their catabolism.


Only 10% of drug is absorbed from intestines, rest is eliminated.

Effect is achieved in about 1-3 months.


Slowly deposited in adipose tissues


Individuals having cardiovascular diseases as prolong QT interval.


Very less common uses.


  • Used in very high doses to produce antihyperlipidemic effects. Slow release preparations are available.
  • Decrease TGs by about 20-80%
  • Decrease LDL by 10%, but when given in combination with other hypolipidemic drugs, decrease in LDL is about 40-60%.
  • Increase HDL levels

Peak effect

Achieved in 1-4 days.

Mechanism of Action

Exact mechanism of action is not established. It is said that:

  • In liver- decrease production of cholesterol, VLDL and LDL.
  • In adipose tissues –inhibit lipolysis, so decrease fatty acids.
  • In plasma –stimulate the activity of lipases and increase clearance of lipoproteins (VLDL)
  • Increase levels of HDL by decreasing their catabolism
  • Increase Apo A-1, major lipoprotein in HDL.

Influence coagulation pathways, decrease fibrinogen  & increase tissue plasminogen activators

B3 acts like vitamin only when activated to NAD.

Oral nicotinamide has vitamin effects only and no anti-hyerlipidemic effects


  1. Hypercholesterolemia (Heterozygous familial hypercholesterolemia)- combination of resins and statins
  2. Hypertriglyceridemia
  3. Combined hyperlipidemia
  4. Severe mixed lipidemia
  5. Decreased HDL
  6. Increased lipoprotein A


1-2 g twice or thrice daily. Sustained release preparations are available.

Toxicity/Adverse Effects

  • GIT – Abdominal discomfort, pain, nausea, vomiting, diarrhea –remedy is to decrease dose, gastric acid inhibitors or antacids not containing aluminium
  • on prolonged use hyperglycemias (carbohydrate intolerance), hyperuricemias, precipitate gout and produce liver damage
  • Hyperpigmentation of skin and acanthosis nigricans (brownish black scaly lesions)
  • Eyes -Blurring of vision and amblyopia (one eye not functioning properly/lazy eye)
  • Can produce vasodilatation leading to cutaneous flushing and postural hypotension esp. if taking antihypertensives (PG mediated), tachyphylaxis when dose increased or used for longer periods
  • Can produce atrial arrhythmias
  • Postural hypotension
  • Birth defects in high doses
  • Pruritis
  • Liver enzyme deranged (increased ALT, acute necrosis, fulminant hepatic failure -rare


1. Pregnancy

2. When patient is taking antihypertensives

3. Gout

4. DM type II

5. Hepatic failure


Better tolerated than Nicotinic acid.  

Acipimox is derivative of Nicotinic acid, given in low doses. It has less toxicity, but potency is also low.

Niaspan has no hepatotoxicity.


1. Resins and statins for type IIa hypercholesterolemia

2. Resins and fibrates for type II b hypercholesterolemia

3. Niacin and statins for type IIb hypercholesterolemia

4. Drugs acting on blood

3. Bile Acid binding resins

  • Basic ion exchange resins, supplied in chloride form. They are neither digested nor absorbed and basically decrease LDL levels. This reduction is around 20-25%.
  • Have little effects on TGs and HDL. Effect is apparent within 3-5 days. Peak effect is visible in 2 weeks.
  • Normally bile acids are absorbed in jejunum, where they exert negative feedback and prevent conversion of cholesterol into bile acids.
  • When bile acid binding resins are used, they bind bile acids and increase excretion of bile acids. No negative feedback occurs, and more conversion of cholesterol into bile acids takes place.
  • There is compensatory increase in LDL receptors in liver.
  • There is more extraction of LDL from plasma.
  • Clearance of IDL, LDL & indirectly VLDL is raised.

Rationale of combining resins and statins

When resins are administered, compensatory increase in cholesterol synthesis occurs (due to decreased cholesterol stores), increasing HMG CoA reductase activity, leading to increased cholesterol synthesis. So HMG CoA reductase inhibitors are also administered.

Adverse effects

1. GIT –abdominal discomfort and constipation (due to increased water intake)

Bloating and dyspepsia (heart burns). Remedy is refrigeration of drug and suspending the drug in liquid medium (evening drug should be suspended in morning)

2. Can aggravate hemorrhoids, relieved by taking dietary fibers

3. Can produce hypochloremic acidosis as bind chloride ions

4. Can produce hypoprothrombonemia (increased bleeding tendency) due to malabsorption of vitamin K.

5. Interfere with absorption of fat soluble vitamins.

6. Can interfere with absorption of lipids, producing steatorrhoea. Common in patients of cholestais and inflammatory bowel disease

7. Interfere with absorption of various drugs like Digoxin, thyroxine, thiazide diuretics, tetracycylines, warfarin and aspirin.

8. Interfere with absorption of folic acid

9. Cholelithiasis –increased cholesterol content of bile.


1. Primary hypercholesterolemias

2. Pruritis –due to choliestasis or due to bile salts accumulation

3. Digitalis toxicity as bind Digitalis


1. Pregnancy

2. Patients of hemorrhoids


Available in form of powders, in packets. Dose is 16-36 g/day. Should not be taken in dry form. Taken with meal.

4. Drugs acting on blood

2. Fibric acid Derivatives


Clofibrate is the 1st drug discovered, but rarely used because of toxic effects. Better drugs with less toxicity and more effects are available.

It acts by:

  • Stimulating activity of lipoprotein lipase enzyme involved in breakdown of TGs. In this way, TGs are decreased.
  • Acting as an agonist at PPAR alpha receptor (peroxisome proliferated activated receptor alpha), involved in fatty acid metabolism.
  • Fibric acid derivatives also cause up and down regulation of genes involved in fatty acid metabolism

Upregulation of apolipoprotein alpha 1 gene.

Down regulation of apolipoprotein C2 gene.

So produce hypolipidemic effects. Also increase:

  • LDL receptor expression in liver under effect of PPAR alpha. More extraction of LDL from plasma occurs.
  • Also decrease TGs synthesis by liver.
  • Decrease TGs by 40-60%
  • Decrease LDL, but to a lesser extent 10-15%
  • Increase HDL by 10-25%


Different kinds of hyperlipidemias (type III)

Regression of xanthomas




Mobilize cholesterol from storage sites

Decrease incidence of coronary heart diseases by 50% when used for prolonged time.


  • Absorption

Absorbed after oral administration. Bioavailability is increased with food.

  • PPC

Plasma peak concentration is achieved in 3-4 hours

  • PPB

Extensively bound to plasma proteins

  • Excretion

Metabolized in liver and predominantly eliminated in urine.

  • T1/2

Half life of Bezafibrate and Gemfibrozil is 2 hours.

Half life of Fenofibrate is 20 hours.

Adverse effects

May produce:

a. GIT disturbances

b. Allergic reactions

c. Myopathies esp. when combined with HMG CoA reductase inhibitors (muscle weakness, tenderness and cramps), less frequently with Fenofibrates. (Rosuvastin amongst statins has lesser incidence of myopathies.

d. Can produce hypokalemias

e. Clofibrate produces blood dyscrasias and cardiac arrhythmias

f. In experimental animals, are found to be teratogenic

g. Liver injuries

h. Can displace oral anticoagulants from protein binding sites

i. Can enhance toxicity of warfarin

j. Increase the incidence of gall stones as increase the secretion of cholesterol in bile.

k. Decrease the conversion of cholesterol into bile acids, so chances of gall stones are more.

l. Cholelithiasis

m. Anemias, decrease WBC count

n. Hair loss


1. Pregnancy

2. Liver disease

3. Gall stones

4. Renal failure

5. Alcohol

6. Children


300 mg, which may be increased up to 600 mg, twice or thrice daily, depending upon the severity of disease. Usually taken with meals.

4. Drugs acting on blood

1. HMG CoA Reductase Inhibitors


Lovastatin and Mevastatin are obtained from natural source, from micro-organisms, penicillin and micromonosporas.

Pravastatin and Simvastatin are semi-synthetic drugs.

Rosuvastatin, Atorvastatin and Fluvastatin are fluorine containing compounds.

Site of action

Main site of action is liver. In liver, they decrease the synthesis of TGs that in turn lead to decrease in VLDL as well as LDL.


Active forms of these drugs are structural analogs of enzyme hydroxyl methyl glutaryl CoA reductase. This enzyme is involved in the synthesis of sterols, and is responsible for the 1st step in that synthesis.

Mechanism of Action:

1.  Competitive Inhibition

These drugs by competitive inhibition interfere with the synthesis of sterols.

2. Up regulation of LDL receptors

They can cause compensatory upregulation of LDL receptors in liver, which can cause increase extraction of LDL from plasma, so LDL levels are again decreased. Thus affect mainly LDL levels.

3. Catabolism

Can also enhance catabolism of LDL. Thus cause:

  • Reduction in LDL about 20-80%
  • Reduction in TGs about 25%
  • However, raised HDL 10-30%

Statins decrease the availability of isoprenyl groups from HMG CoA pathway, leading to:

I. decreased prenylation of Rho proteins, decreasing the activity of Rhokinase, decreasing the incidence of new coronary events.

II. decreased prenylation of Rab proteins, leading to decreased accumulation of Aβ in neurons, decreasing the manifestations of Alzheimer’s disease.

Statins decrease the oxidative stress by LDL and decrease atherosclerosis.

Statins stabilize the plaque, decreasing the chances of embolism.

Statins increase the NO.


  • Administration

Administered at bed time. Since activity of HMG CoA reductase is maximum at night.

  • Absorption

Incompletely absorbed after oral administration.

  • Extensive first pass metabolism

Bioavailability is increased when given with meals, so given with food.

  • PPC

Peak plasma concentration is achieved in 2-4 hours.

  • PPB

These drugs have extensive plasma protein binding.

  • Excretion

Mainly excreted in bile. About 10% eliminated in urine.

  • T1/2

Most statins have half life of 2 hours, except atorvastatin (14 hours) and Rosuvastatin (19 hours).


1. Familial hypercholesterolemia (due to increased LDL) not used in children

2. Acute coronary syndrome

Adverse effects

Remarkably well tolerated except for a few adverse effects.

1. GIT –abdominal discomfort, gastric irritation, diarrhea

2. Skin rashes, urticaria, allergic manifestations, and lupus like syndrome

3. May cause myopathies, where there is muscle tenderness, muscle cramps, fatigue. This myopathy is seen when given with Verapamil and Amiodarone.

4. Rabdomyolysis can lead to myoglobinurea and renal damage. This muscular injury is manifested by a rise in serum creatinine kinase levels.

5. These drugs cause polyneuropathies.

6. They can produce liver damage and increased serum transaminase levels, due to high 1st pass metabolism.

7. In experimental animals, are found to be teratogenic.



Liver diseases


Started from 20 mg and may be increased up to 80 mg, given twice or thrice daily, depending upon the severity of hyperlipidemias.

Drug Interactions

Simvastatin, Atorvastatin and Lovastatin are metabolized through CYP3A4. Drugs that inhibit CYP3A4 like Ketoconazole, Macrolides and Cyclosporins, can increase levels of statins, when given together.

Drugs like Phenytoin and Rifampicin act as enzyme inducers.

Rosuvastatin and Fluvastatin are metabolized through CYP2C9. Drugs that inhibit the cytochrome CYP2C9 like Metamindazole, Cimetidine and   Ketoconazole increase the levels. 

4. Drugs acting on blood

Hypolipidemic Drugs

Drugs that lower lipid and lipoproteins levels in the blood are known as hypolipidemic drugs.

The first measure in controlling hyperlipidemias is dietary restriction. However, if it proves unsatisfactory, hypolipidemic drugs are prescribed.

Hypolipidemic drugs have attracted considerable attention since they prevent cardiovascular diseases by retarding atherosclerosis in hyperlipidemic individuals.

 Lipid transport:

  • Carried in plasma in form of lipoproteins, after getting associated with several apolipoproteins.
  • Plasma lipid concentrations are dependent upon the concentration of lipoproteins.
  • Lipoprotein globules consist of core of triglyceride and cholesterol esters. The outer polar layer has phospholipids, apoproteins and free cholesterol.
  • Divided into 6 classes depending upon particle size and density. These are:

a. Chylomicrons

b. Chylomicron remnants


d. IDL

e. LDL

f. HDL

a)  Chylomicrons are the largest lipoproteins containing about 90% triglycerides and about 5% cholesterol.

b)  Chylomicron remnants contain more cholesterol than triglycerides.

c)  VLDL contains 50-60% triglycerides and 10% cholesterol.

d)  IDL, just like chylomicron remnants, contain more cholesterol than triglycerides.

e) LDL contain 50% cholesterol and 5% triglycerides.

f)  HDL contain 20% cholesterol and 10% triglycerides.

  • Dietary lipids are absorbed in the intestine with help of bole acids and chylomicrons are formed.
  • They are passed into lacteals and reach blood stream.
  • During passage via capillaries, the endothelial lipases hydrolyze TGs and convert them into fatty acids, which are carried to muscles to be utilized as energy source or are taken up by fat cells, where they are reconverted into fat cells.
  • Remaining part left is chylomicron remnant, which is engulfed by liver, which has receptors for it.
  • Free cholesterol liberated is either stored in liver cells or excreted in bile in form of bile acids.
  • Liver secretes VLDL which contain more TGs than cholesterol esters.
  • Lipases act and convert it into IDL, which contains more cholesterol than TGs
  • Half IDL is taken up by liver cells, while remaining half loses TGs and becomes LDL, which contains cholesterol.
  • LDL circulates in plasma for a long time and uptake into cells is dependent upon the needs of cells for cholesterol.
  • Cholesterol ester present in LDL is de-esterified and mainly used in cell membrane formation.
  • The cholesterol released from degradation of membrane is incorporated into HDL. It is then esterified with help of enzyme and transferred back to VLDL or IDL. Thus completing the cycle.
  • Excess lipoproteins in plasma are phagocytosed by macrophages for disposal.
  • If too much lipoprotein is to be degraded in this manner, excess of cholesterol is in atheromas i.e. arterial walls and xanthomas i.e. in skin and tendons.
  • Raised levels of VLDL, IDL, LDL and rarely those of chylomicrons and chylomicron remnants all are atherogenic.
  • Raised levels of HDL, however, may be protective since HDL facilitates the removal of cholesterol from tissues.

 Causes of Hyperlipidemias:

a. Primary

  • Genetic
  • Multifactorial


  • Diabetes
  • Smoking
  • Hypertension
  • Nephrotic syndrome
  • Alcoholism
  • Drugs

 Types of Hyperlipidemias

  • Type 1 (Familial Hyperchylomicronemias)(mainly increased VLDL levels)
  • Type 11A (Familial Hypercholesterolemia) (mainly increased LDL levels)
  • Type 11B (Familial Combined Hyperlipidemias) (mainly increased LDL and VLDL levels)
  • Type 111 (Familial Dysbetalipoproteinemias) (mainly increased VLDL levels)
  • Type IV (Familial Hypertriglyceridemia) (mainly increased VLDL levels)
  • Type V(Familial Mixed Hypertriglyceridemia) (mainly increased LDL and VLDL levels)


HMG CoA Reductase Inhibitors (also known as statins)

  •  Lovastatin
  •  Mevastatin
  •  Pravastatin
  •  Simvastatin
  •  Rosuvastatin
  •  Atorvastatin
  •  Fluvastatin
  •  Cerivastatin

Fibric Acids Derivatives (also called fibrates)

  •  Clofibrate
  •  Fenofibrate
  •  Bezafibrate
  •  Ciprofibrate
  •  Gemfibrozil

Bile Acid Binding Resins

  •  Cholestyramine
  •  Colestipol
  •  Colesevelam

Butylated Hydroxytoluene

  • Probucol


  •  Nicotinic acid
  •  Nicfuranose
  •  Acipimox

Cholesterol Absorption inhibitors

  • Ezetimibe

Fish Oils

Omega-3 marine triglycerides


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HMG CoA Reductase Inhibitors

Fibric Acid Derivatives

Bile Acid Binding Resins

Probucol and Nicotinamides

Cholesterol Absorption Inhibitors, Fish Oils and Orlistat

4. Drugs acting on blood

Thrombolytics and Fibrinolytics

As the name suggests these drugs:

a. break down thrombosis – Arterial / Venous

b. Fibrinolysis –degrade fibrinogen and fibrin

so clot formation decreases.

Naturally when endothelial injury occurs, after some time clot is formed, and endothelial tissue releases tissue plasminogen activator. This acts on plasminogen converting it into plasmin, when acts on fibrin polymers, breaking them down, leading to thrombus breakdown.


Not only break pathological thrombi but also normal haemostatic plugs in body, which are protective in nature.

There is a generalized lytic state. Increased internal bleeding and hemorrhage might occur, thus patients are carefully selected.

 1. Streptokinase

Protein in nature obtained from streptococci. It forms one to one complex with plasminogen, activating it, plasminogen forms and fibrin polymer breakdown takes place.

It is given parentally, having half life of 2 minutes.

2. Urokinase

Enzyme obtained from fetal kidney cells, grown on tissue culture.

Longer half life than streptokinase of about 15 minutes.

3. Anistreplase

Anisoylated plasminogen streptokinase activator complex (APSAC), a complex of human plasminogen and streptokinase obtained from streptococci. The active site of enzyme is covered with acyl group.

On administration, acyl group is hydrolyzed, the complex and plasminogen is activated.

Drug has more clot selectivity.

Thrombolytic duration of action is 70 minutes.

Tissue plasminogen activator (t-PA)

Naturally present in the body. Also prepared by recombinant DNA technology. Different preparations are available:

1. Alteplase –mutant form of tissue plasminogen activator

2. Reteplase – less fibrin specific than alteplase

3. Tenecteplase – more fibrin specific


1. Acute MI

Main use. Proper patient selection must be done in emergency. Thrombolytic therapy has best outcome when administered as early as possible. Best results are obtained within 6 hours of attack, although administered up to 24 hours, the benefits decrease as time from onset of attack is increased. Administered in patients with ST elevation, indicating patient has complete obstruction of coronary vessel by clot, so needs this treatment.

2. Pulmonary embolism

3. Severe DVT – sup. vena caval syndrome
4. Ascending thrombophlebitis – ileofemoral vein
5. Cerebrovascular ischemia with stroke

Adverse effects

1. Bleeding –due to lytic state.

All contraindications of heparin are same here.

2. Micro-emboli –when thrombus breaks
3. Arrhythmias –due to sudden reperfusion after acute MI
4. Allergy –streptokinase is obtained from streptococci, which are antigenic in nature, body may form antibodies, esp. in patients with streptococcal infections.

If suspect infection in the last 2 weeks, then not given.  


Bleeding tendency

 Fibrinolytic Inhibitors

Aminocaproic acid

Similar in structure to Lysine. As the name suggests, its action is opposite to fibrinolytics. It binds plasminogen and inhibits the binding of fibrinogen with plasmin.

Tranexamic acid

Analogue of aminocaproic acid, used orally and parentally.


  1. Bleeding –adverse effect of fibrinolytic therapy
  2. Adjunctive in hemophilia –dental extraction etc. when chances of bleeding
  3. Prophylaxis –intracranial  aneurysms to prevent bleeding
  4. Postsurgical bleeding –esp. GIT / prostate
  5. Bladder hemorrhage –due to cystitis, drugs or radiations
  6. Menorrhagia

 Adverse effects

1. Thrombosis

2. Hypotension

3. Myopathy

4. GIT disturbance


  1. Disseminated intravascular coagulation (DIC)
  2. Upper genito-urinary tract bleeding – involving kidney, ureter.
  3. Clot Colic

Hemeaturia occurs due to urinary tract bleeding, clot forms, leading to clot colic, which is not dissolved as giving therapy

Serine Protease inhibitor

Aprotinin (serpin) acts directly on plasmin, inhibiting its actions. It used during surgeries where extracorporeal circulation (outside body) is required (e.g. liver transplant/cardiac bypass).

4. Drugs acting on blood

Antiplatelet Drugs

Antiplatelet drugs affect the fluidity of blood in thromboembolic conditions.

Platelet Plug:

Normally when endothelial injury occurs, it exposes tissues to platelets, leading to activation and aggregation.

During this activation, different substances are synthesized and released, leading to:

a. platelet aggregation

b. vasoconstriction

The important ones are:

–        Thromboxane A2

–        ADP

–        Serotonin

Conformational change occurs in IIb/IIIa receptors present on platelet surface to which fibrinogen binds, leading to anchoring with other platelets and endothelial lining.

Antiplatelet drugs either:

1. act on these receptors or

2. inhibit the release of these substances


1. Thromboxane-A2 inhibitor

–        Aspirin

2. ADP receptor inhibitors

–        Clopidogrel

–        Ticlopidine

3. Glycoprotein IIb/IIIa receptor blockers

–        Abciximab

–        Eptifibatide

–        Tirofiban

4. Phosphodiesterase inhibitors

–        Dipyridamole

–        Cilostazol

 Thromboxane-A2 Inhibitor Aspirin (details with NSAIDS)

Aspirin is normally present in platelets

Arachidonic acid is converted into thromboxane A2 by cyclooxygenase I (COX-I) enzyme.

This enzyme is inhibited by aspirin, acetylating it irreversibly.  

Thus, no thromboxane A2 is produced responsible for platelet activation and aggregation.

Vasoconstrictor as well as vasoconstriction is decreased.


75 – 300 mg/day, but in certain patients for prophylaxis of MI, 325 mg are given.

Advantages of low dose

1. Toxic effects (GIT) are less

2. Antiplatelet effects but production of prostacyclines are not affected (vasodilator substances beneficial in cardiac patients).

 ADP Receptor Inhibitors

  • Thienopyridine derivatives
  • 2 drugs acting on purinergic receptors – P2Y1 & P2Y12
  • Irreversible binding –staying for life of platelets (7-10 days)
  • When ADP binds, it leads to platelet aggregation, so these drugs prevent ADP binding.
  • Both drugs are prodrugs, activated after oral administration


  • Ticlopidine is used along with aspirin producing synergistic effects, as both have different sites of action.
  • It produces more side effects including:

a. GIT disturbance

b. Leukopenia

c. Thrombotic thrombocytopenic pupura-hemolytic uremic syndrome (TTP-HUS)

Side effects involving while blood cells are visible during the first three months, so repeated counts are taken during this time.

Dose 250 mg twice daily


Once daily dose of 75 mg OD. It has fewer side effects.

 Glycoprotein IIb/IIIa Receptor Blockers

Receptors are present on platelet surface to which fibrinogen, fibronectin, vitronectin, von Willebrand factor bind, leading to platelet activation and aggregation with one another and endothelium, leading to clot formation. These drugs inhibit this binding and prevent platelet aggregation.

Individuals lacking these receptors suffer from Glanzmann’s thrombasthenia, leading to bleeding tendency.


Chimeric (part animal part human source). It not only effects IIb/IIIa receptors only but also Vitronectin receptors on other tissues, leading to side effects like:

a. Bleeding

b. thrombocytopenia

It is mostly used with heparin, aspirin (anticoagulants) in patients of angioplasty.


Peptide analog having same structure as the terminal part of fibrinogen, so instead of fibrinogen, it binds receptors, blocking them to which fibrinogen cannot bind.


Nonpeptide small molecule having same action as eptifibatide.

 Phosphodiesterase Inhibitors


It has two main functions:

  1. Blocks adenosine uptake – adenosine acts on A2 receptors, increasing cAMP.
  2. Inhibits phosphodiestrase which degrades AMP and GMP to cAMP / cGMP, their levels rise, producing antiplatelet effect
  3. Has vasodilator effect in addition

It is not a powerful drug, so combined with other drugs.

a. Aspirin (25mg) + Dip. (200mg) –in patients having cerebrovascular ischemia because of stroke or transient ischemic attack (TIA)

b. with warfarin in patients having prosthetic valves


Phosphodiesterase inhibitor used for intermittent claudication

 Uses of Antiplatelet drugs

1. Cerebrovascular diseases – TIA / stroke

2. Coronary artery diseases – unstable angina / MI

3. Peripheral arterial diseases

4. Coronary bypass implants / stents

5. Prosthetic heart valves

6. Arterial graft

7. Arterio-venous shunts

4. Drugs acting on blood

3. Fondaparinux, Heparinoids and Direct Thrombin Inhibitors


Chemistry – synthetic pentasacchride

Mechanism of Action

Acts by inhibiting factor X.


Long half life of 17-21 hours.

Given parentally.


Used instead of heparin in cases where heparin induced thrombocytopenia occurs, as no HIT is seen with this.

Advantage – HIT

Disadvantage – antagonism

No antagonist acts, as protamine sulphate is ineffective.

Idraparinux – sulfated derivative of Fondaparinux, having an even longer half life.


These are related with heparin.

Heparan Sulfate

Natural –in mast cells

Commercially prepared as well.

The difference is that polymers of heparin sulphate are less modified than heparin.

Danaparoid is an example.

Advantage -HIT

Direct Thrombin Inhibitors

Mechanism of Action

Hirudin, Lepirudin and Bivalirudin are bivalent and bind to two sites on thrombin directly:

i. Active catalytic site

ii. Substrate recognition site

Argatroban and Melagatran are small molecules and bind only one site; the active catalytic site.


Hirudin occurs naturally in leeches.

Rest are synthesized by recombinant DNA technology.

Monitoring & Pharmacokinetics

All are administered parentally. Therapeutic efficacy is measured by APTT.


40% of the patients form antibody complex with lepirudin and these complexes are unable to be excreted through kidneys. They are given with caution in renally impaired patients.


It is metabolized by the liver, which is its main eliminating organ.

Thus patients with renal insufficiency are administered Argatroban, while those with hepatic insufficiency, Lepirudin.


  • In surgery for Reattachment of digits (even leeches were used)
  • HIT
  • Coronary angioplasty

Adverse effects

  • Renal
  • Anaphylactic reaction –with Lepirudin


It is given orally and is a prodrug. It is changed into Melagatran.

Advantage –HIT

4. Drugs acting on blood

2. Warfarin


During early 20th century, hemorrhagic diseases occurred in cattle that ate spoiled fodder (spoiled sweet clover silage). Chemists at Wisconsin Alumni Research Foundation extracted Bishydroxycoumarin responsible for this disease.

Afterwards warfarin was synthesized as coumarin derivative.

It was first used as Rodenticide

Afterwards during second half of 20th century, it was used as oral anticoagulant.


Mainly two chemical compounds are chosen for oral administration:

  1. Coumarin –commonly used like Warfarin
  2. Phenindione

Administered as racemic preparation, two enantiomers or isoforms exist:

1. S warfarin (levorotatory) 4 times more potent

2. R warfarin (dextrorotatory)

Mechanism of Action

Factor II, VII, IX, X are the glutamic acid residues and need to be carboxylated to alpha carboxy glutamic acid. This is required so that the Ca++ bridge with epithelium is formed.

During carboxylation, vitamin K is converted from reduced to oxidized form.

Oxidized form has to be converted back into reduced form, by vitamin K epoxide reductase for the reaction to continue.

Thus, reduced form is inhibited, and the process is suppressed.

The synthesis of factor II, VII, IX, X, protein C and S is suppressed, as no carboxylation occurs due to non-availability of reduced form of vitamin K.

The action of warfarin is delayed because of two reasons:

a. Delayed onset

Longer half life of about 40 hours, steady state is achieved after 2 days.

b. Anticoagulant effect

Already synthesized clotting factors are available in blood, warfarin effects can only be seen when new factors are synthesized.

As warfarin is given in racemic form, so S warfarin is 3-5 times potent than R warfarin.

Up till now no separate preparation has been prepared, and are given in combination.

Resistance to warfarin

Resistance to warfarin is genetic, due to mutation in epoxide reductase.

Administration & monitoring

Monitored by PTT and INR.

PT (Common and Extrinsic Pathway) – time taken for clotting of citrated plasma after addition of Ca+2 and standardized reference thromboplastin (12-14 s). Role of thromboplastin is not present in this clotting time as it is added from outside, so that only prothrombin is active.

Should be maintained at 2.5-3.5 times normal in warfarin therapy.

Different animal sources are used in different labs, due to differences in kits, various variations in prothrombin time are observed, and thus better method is introduced.

INR – International Normalized Ratio, which is the prothombin time ratio of a patient with reference value(2 – 3.5)

ISI is the international sensitivity indexEach thromboplastin is assigned a specific throboplastin number.

If INR is <1.5 there are more chances of thromboembolic phenomenon.

If INR is >4 there are more chances of bleeding.

Normal medicinal range is 2-3, while that for prosthetic heart valves is up to 3.5


Route of Administration

Most commonly orally, other routes include parenteral and rectal. After oral route, bioavailability is 100%.


Absorbed in GIT




Highly bound to plasma proteins (98-99%)

BBB & Placenta

Can cross BBB and placenta, thus not administered in pregnancy


Half life of S type is less than 25 hours.

Half life of R type is up to 50-60 hours.

On average, half life is 40 hours.


Metabolism is different for S and R types.

S type is metabolized by cytochrome P2C9

R type is metabolized by cytochrome P1A2, P3A4 and P2C19.


Excreted in urine.

Pharmacological Actions

1. Anticoagulant action –delayed onset (48hours) because clotting factors already present are not affected)

2. Also decreases synthesis of endogenous anticoagulants (protein C and S)

Clinical Uses

Prevention of thromboembolism

Not given in emergency, heparin is started, while warfarin is started as well. After 3-4 days, heparin is stopped, and then only warfarin is used.

Differences from heparin

Given in emergencyNot given in emergency
Can be given in surgeryCannot be given in surgery
Can be given in pregnancyCannot be given in pregnancy

Adverse Effects

1. Bleeding

If minor and patient is stable, only drug is discontinued, patient is monitored.

a. .Phytonadione (K1)

If INR is greater than 5, vitamin K preparation is given orally or I/V according to the need of patient. Action of this is only after 12-24 hours.

b. FFP

If INR is much higher, fresh frozen plasma is administered.

c. Different preparations of clotting factors are administered.

As inhibits clotting factors and protein C (half life 8 hours) and S (natural anticoagulant).

First natural anticoagulant is affected, and are not formed, but small thrombi are formed, especially patients deficient in protein C and protein S. There are greater chances of skin and tissue necrosis (fatty tissue necrosis).

2. Skin / Tissue necrosis

Occurs early in adults.

3. Teratogenicity

As warfarin can cross placental barrier, it is teratogenic and inhibits gamma carboxylation of proteins. In fetus bone and soft tissues are not properly formed.  Also hemorrhagic disorders occur in fetus.

4. As it decreases activity of protein C, it leads to cutaneous necrosis and infraction of breast fatty tissue, intestine and extremities (rare)

5. warfarin induced depression of protein C also leads to venous thrombosis

Warfarin Sensitivity – CYP2C9

Polymorphism occurs, less dose is required, as unable to metabolize at the natural rate (rate decreased)

Warfarin Resistance – VKORC1

Polymorphism occurs, leading to change in dose. In certain patients larger dose is required to produce therapeutic effects.

Dosing algorithms are prepared taking genotype, etc. in account, to calculate individualized dose.

Drug Interactions

Occur in two categories:

1. Pharmacokinetic

Mostly due to:

i. enzyme induction

ii. enzyme inhibition

iii. decreased PPB

1. Pyrazolone, Phenylbutazone and Sulfinpyrazone decrease metabolism of S-warfarin and displace albumin bound warfarin leading to increased warfarin and increased anticoagulant effects (increased risk of bleeding)

Effects include:

i. Augment hypoprothrombinemia

ii. Decrease platelet function

iii. May induce peptic ulcer disease

2. Barbiturates and Rifampicin (enzyme inducers) increase metabolism of warfarin, decreasing its effects.

3. Metronidazole, Trimethoprim-sulfamethoxazole (co-trimoxazole) and Fluconazole decrease metabolism of S-warfarin, increasing its effects.

4. Amiodarone, Disulfiram and Cimetidine decrease metabolism of both S and R warfarin, enhancing the effects.

5. Cholestyramine binds warfarin in intestine and decreases absorption and bioavailability.

Increased PTDecreased PT

2. Pharmacodynamic

Mostly due to:

i. Synergism

ii. Competitive antagonism (vit. K)

iii. Altered physiologic control loop for vit. K (hereditary resistance to oral anticoagulants)

iv. Impaired hemostasis, decreased clotting factor synthesis as in hepatic disease

a. Aspirin (anti-platelet), hepatic disease and hyperthyroidism (increase turnover of clotting factors) increase warfarin effects.

b. Third generation cephalosporins eliminate bacteria in intestinal tract that produce vitamin K. Also decrease vitamin K like warfarin effects.

c. Vitamin K increases synthesis of clotting factors, decreasing the effect of warfarin.

d. Diuretics (Cholothalidone and Spironolactone) increase clotting factor concentration, decreasing effects.

e. Hereditary resistance decreases effects.

f. Hypothyroidism increases turn over of clotting factors.

Increased PTDecreased PT
DrugsAspirin (high doses)Cephalosporins, third generationHeparinBody FactorsHepatic diseasesHyperthyroidismDrugsDiureticsVitamin KBody FactorsHereditary resistanceHypothyroidism