2. Anti-platelet/ Anti-aggregation drugs

Dr. Subasini

Faculty of Pharmacology

Tishk International University.

Pharmacy Grade – IV

Fall Semester 2021-2022

Anti-platelet Drugs

• Platelets first stick to damaged blood vessel wall and aggregation occurs which lead to release of ADP, TXA2, serotonin and other substances that promote further aggregation by activating Gp IIb/IIIa receptors on the platelet surface.

Anti-platelet Drugs

• Main drugs acting as antiplatelet agents are

1. TXA2 synthesis inhibitor (aspirin),

2. ADP antagonists (clopidogrel and ticlopidine)

3. Gp IIb/IIIa antagonists (abciximab, tirofiban, eptifibatide).

Classification

New drugs

Newer drugs

Aspirin and Dipyridamole

• Aspirin inhibits thromboxane synthesis but does not inhibit the enzyme thromboxane synthetase.

• For antiplatelet action lowest doses of aspirin are required (40-325 mg).

• Dipyridamole is another drug that acts by inhibiting phosphodiesterase (which breaks down cAMP) resulting in increased cAMP that potentiates prostacyclins and thus anti-aggregation

ADP- Antagonist drugs

• Ticlopidine, clopidogrel and prasugrel act as irreversible antagonists of P2Y12 receptor of ADP. Ticagrelor and cangrelor are direct-acting reversible P2Y12 receptor antagonists

• These drugs interfere with the activation of platelets by ADP and fibrinogen.

• Ticlopidine and clopidogrel are prodrugs and are converted to active metabolites in the liver by CYP2C19.

ADP- Antagonist drugs

• Ticlopidine causes severe neutropenia (Absolute neutrophil count < 500/mL) and thrombocytopenia and thus less commonly used.

• whereas clopidogrel is better tolerated. Most common side effects of these drugs are gastrointestinal.

• Prasugrel is strong antiplatelet drug as compared to ticlopidine or clopidogrel.

• It is faster acting than clopidogrel. • However, it also has higher risk of fatal bleeding and

thus should be avoided in elderly patients (> 75 years old) and those with history of stroke.

Gp IIb/IIIa antagonists

• Gp IIb/IIIa antagonists are strongest antiplateletdrugs as they block aggregation induced by all agonists.

• Abciximab is a monoclonal antibody against this receptor and is not antigenic.

• Eptifibatide and tirofiban are other drugs in this category

• Abiciximab has long half-life (days). • In addition to bleeding, thrombocytopenia is the

most serious complication of these agents.

Clinical uses

• Antiplatelet drugs are used for prophylaxis of MI (aspirin is used most commonly),

• Cerebrovascular disease and in artificial heart valves (dipyridamole + warfarin is preferred).

New Antiplatelet Agents

• Ticagrelor and cangrelor are direct-acting reversible (ADP)P2Y12 receptor antagonists.

• Ticagrelor is orally effective. As compared to clopidogrel, it produces greater and more predictable antiplatelet action.

• Cangrelor is intravenous reversible P2Y12 receptor antagonist.

• Vorapaxar is an orally active inhibitor of thrombin receptors on platelets called protease-activated receptor 1 (PAR-1). It has recently been approved as antiplatelet drug

Fibrinolytics/Thrombolytics

• Fibrinolytics are the drugs which activate plasminogen to form plasmin and thus help in lysis of thrombus.

• Important fibrinolytic drugs are streptokinase, anistreplase urokinase, alteplase, reteplaseand tenecteplase.

Plasma Expanders• These are high molecular weight substances that

exert osmotic effect and retain fluid in blood vessels when infused i.v.

• These are used to correct hypovolemia due to blood loss as in trauma.

• The agents used are: Albumin, dextran, Polygeline and hetastarch.

• Dextran-70 is longer acting (24 hours) whereas dextran-40 is rapid but short acting.

• Plasma expanders are contraindicated in severe anemia, heart failure, pulmonary edema, liver and kidney failure

HAEMATINICS

• Haematinics such as iron, vitamin B12, folic acid, etc. arerequired for the formation of blood and are used in thetreatment of anaemia.

• Causes of anaemia:1. Decreased formation of RBCs: Deficiency of essential

nutrients—iron, vitamin B12, folic acid, etc.2. Increased destruction of RBCs: Haemolytic anaemias,

sickle-cell anaemia.3. Depression of bone marrow: Cytotoxic drugs, radiation, toxins.4. Excessive blood loss: Due to hookworm infestation, bleeding from gastrointestinal tract (GIT) and other sites

Oral and Parenteral Forms of Iron• a. Oral iron preparations are:• Ferrous sulfate• Ferrous gluconate• Ferrous fumarate• Ferrous succinate• Ferrous acetate• Ferrous carbonate.

• b. Parenteral iron preparations are:• IM iron dextran complex iron—Sorbitol citric acid complex• IV iron dextran, saccharated iron dextran.

• Iron Dextran is the preparation of choice for parenteral iron therapy. Each ml of iron dextran contains 50 mg of elemental iron

Adverse effects of oral iron are nausea, vomiting, epigastric discomfort,

dyspepsia, metallic taste, constipation or diarrhoea,

and staining of teeth

Factors affecting iron absorption

• Iron absorption is facilitated by acidic pH ofthe stomach, ascorbic acid, cysteine, etc.,which reduces the ferric iron to ferrous form.Iron-deficiency states also increase theabsorption of iron.

• Iron absorption is inhibited by excess ofphosphates, oxalates, phytates, etc.

• Milk, antacids and tetracyclines reduce ironabsorption by forming insoluble complexes.

Golden points1. Daily requirement of iron is

Adult male 1 mg

Menstruating female 2 mg

Pregnant female 3-5 mg

2. Liver, egg yolk, beans and dry fruits are good source of iron whereas milk and its products are poor sources

3. Iron is absorbed mostly in the duodenum in the ferrous form (Fe2+)

4. Ascorbic acid and also gastric acid (HCl) increases the iron absorption.

5. After absorption, iron can either be stored as ferritin or it is transported with transferrin to be utilized in the formation of blood.

6. When there is excess of iron in the body, it combines with apoferritin to form ferritin

7. Iron is used for prophylaxis or treatment of iron deficiency anemia (microcytic hypochromic anemia)

8. Treatment with oral iron should be continued for 3–6 months. This will correct the anemia and replenish iron stores.

9. For prophylaxis of iron deficiency, 200 mg ferrous sulphate once daily is enough.

10. In pregnancy, iron should be started in the second trimester.

11. Major adverse effects of oral iron that result in epigastric pain, nausea, vomiting and metallic taste etc

12. Vitamin B12 present in animal foods (liver, kidney, meet, cheese, egg yolk etc.)

13. For antiplatelet action lowest doses of aspirin are required (40-325 mg).

14. Ticlopidine, clopidogrel and prasugrel act as irreversible antagonists of P2Y12 receptor of ADP

15. Ticlopidine and clopidogrel are prodrugs and are converted to active metabolites in the liver by CYP2C19.

16. Prasugrel is strong antiplatelet drug as compared to ticlopidine or clopidogrel

17. Gp IIb/IIIa antagonists are strongest antiplatelet drugs as they block platelet aggregation

18. Abciximab is a monoclonal antibody against this Gp IIb/IIIa receptor

19. Warfarin shows a number of drug - drug interactions because highly plasma protein binding

20. Haparin does not cross the placenta and is thus anticoagulant of choice during pregnancy

Acute Iron Poisoning• It is seen frequently in young children. The manifestations are

nausea, vomiting, epigastric pain, bloody diarrhoea, dehydration,cyanosis, drowsiness, hyperventilation, metabolic acidosis,convulsions, coma and death.

• Treatment• Supportive measures: Airway, Breathing, Circulation, Fluid and

Electrolyte and acid–base balance should be maintained.• Whole bowel irrigation to remove unabsorbed iron pills from the

GIT.• Intravenous Diazepam to control convulsions.• Specific therapy• Desferrioxamine, a potent iron chelating agent, is administered by

i.v. infusion or intramuscularly depending on the severity ofpoisoning. It binds with iron in the blood and facilitates itsexcretion.

DRUg OF ChOicE

• Condition• Iron deficiency anemia• Megaloblastic anemia• Pernicious anemia• Iron poisoning• Acute• Chronic• Deep vein thrombosis• Prophylaxis• Initiation of therapy• Heparin overdose• Warfarin overdose• Myocardial Infarction• Fibrinolytic overdose

• Drug of choice• Ferrous sulphate• Folic acid/ Vitamin B12• Vitamin B12• --• Desferrioxamine• Deferipirone• --• Warfarin• LMW heparin + warfarin• Protamine sulfate• Vitamin K• Thrombolytics (Reteplase)• Tranexamic acid or Epsilon Amino

Caproic Acid

Key points

• Streptokinase is obtained from b hemolytic streptococci.

• Anistreplase is formed by combining streptokinase with Lys-plasminogen

• Urokinase is isolated from human urine and is not antigenic.

• Alteplase, reteplase and tenecteplase are recombinant tPA.

• Reteplase and tenecteplase (longest acting)are known as bolus fibrinolytics

References

• Rang HP, Dale MM, Ritter JM and Moore PK (2007). In:

• Pharmacology. 6th edition, Churchill Livingstone, USA.

• Tripathi KD (2003). In: Essentials of Medical Pharmacology. 5th edition, Jaypee Brothers, Medical publishers Ltd, New Dehli.

• Finkel R, Cubeddu LX and Clark MA (2009). In: Lippincott’s Iillustrated Reviews Pharmacology. 4th edition, Lippincott Williams and Wilkins, China

Questions

• Name 5 antiplatelet drugs

• How Aspirin acts as antiplatelate drug? Name 5 clinicalconditions where its dose is 75–100 mg and why?

• Define thrombolytics or fibrinolytics.

• Name 5 thrombolytics. How they act?

• What is anemia? What are the causes?

• Define and classify hematinics. Name 5 iron rich foods.

• Comment on milk with antacids and tetracyclines.

• What are the oral irons? In most cases of iron therapy,which route is preferred?