Blood Pharmacology-Include Haematinics, Fibrinolytics & its Antagonist & Anti-platelet Agents for MBBS/BDS

1. Haematinics

2. • These are the agent required in the formation of blood & used for the treatment
of Anemia
• E.g.-Iron, vitamin B12, folic acid (Main Haematinics)
• Accessory hematinic-Vit-C, Riboflavin, Pyridoxine & certain minerals like Cu,
Co & Mn
• In anemia-↓ oxygen-carrying capacity of blood due to a ↓ in blood hemoglobin
level and number of circulating RBCs
• 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

3. • Iron is an essential element of the body.
• Dietary Sources:- liver, fish, dry fruits, jaggery, spinach, banana, meat
• Approximate distribution:-
70%-Hemoglobin
10%-Myoglobin
10-20%-stored as ferritin & Hemosiderin
<1%-Enzyme(Cytochromes) & transferrin
Daily requirement of iron:-
Adult male-1mg/day
Menstruating Female-2mg/day
Pregnant female-3-5mg/day
Iron(Fe)

4. • Pharmacokinetics:-
Dietary iron [mostly Fe3+]
Non-haeme iron
In stomach
Fe3+ Fe2+
Ascorbic acid, SH-
containing Amino acid in
Gastric acid
 Iron Absorption inhibited by Coffee, Tea,
Antacid, Phosphates(rich in egg yolk),
Tetracycline
 Site for absorption-duodenum, proximal
jejunum by active transport
 Rate of Absorption Depends on the ratio of
Apoferritin to ferritin in intestinal mucosa
Apoferritin-iron complex
protein
On demand(↑Body iron requirement ):-
Iron transported from Mucosal cell to bone
marrow by forming complex with transferrin
Mucosal block
In the intestinal mucosal cell
Bo
 Small amount of Irone is excreted via urine

5. • Iron balance:-
1. Maintained by changes in absorption regulated by the concentration of
transferrin & ferritin in mucosal cell
2. In iron deficiency:- ↑transferrin & ↓ferritin
3. In iron overload-↓transferrin & ↑ferritin
Treatment of Iron deficiency Anaemia:-
Rx by using Iron preparation
Preparations of iron
Oral preparation Parenteral preparations
 Ferrous sulphate
 Ferrous gluconate
 Ferrous fumarate
 ferrous succinate
 Iron choline citrate
 Ferric ammonium citrate
 Iron sorbitol citric acid complex
 Iron dextran complex
 Ferric carboxymaltose
 ferrous sucrose

6. Oral preparation:-
• Preferred route-orally
• Fe2+ salts-better absorption
• Ferrous sulphate:- (most economical preparation)
• Iron content-20% (hydrated salt) and 32% (dried salt) elemental iron
• Absorption better-empty stomach
• Ferrous gluconate:- contins 12% elemental iron
• Ferrous Fumerate-33% elemental iron-stable moderately soluble in water &
tasteless
• Side Effect of oral therapy:-
• Poor compliance due to GI distress like epigastric pain,nausea,vomiting,metalic
taste(if taken with or after Food)
• Black stool-due to GI bleeding,staining of teeth (mainly with liquid preparation)

7. Parental preparation:-
• Indication for Parental therapy
Poor oral compliance
Severe intolerance
Malabsorption
Severe anaemia in the late stages of pregnancy
Renal disease
Iron sorbitol citric acid complex (Jectofer):-
Used in i.m. route (i.v. route- cause iron toxicity due to more free iron)
Iron dextran complex (Imferon):- can be given I.V. & I.M.
Use-severe deficiency with chronic bleeding
Pt. unable to tolerated to oral preparation(bowel upset)
SE:-hypersensitivity reaction (preventable)

8. • Ferric carboxymaltose and ferrous sucrose:- i.v. less risk of hypersensitivity
reaction
• Macromolecule iron complex contains ferric hydroxide core stabilized by
carbohydrate cell
• Not used in children-<14year
• Side effects of parental preparation:-
• Painful, may cause abscess and discoloration of the skin at the site of injection.
• Systemic side effects-headache, pyrexia, nausea, vomiting, arthralgia,
lymphadenopathy, urticaria anaphylactic reaction
• Therapeutic uses of iron:-
1. To treat iron-deficiency anaemia (microcytic hypochromic anaemia)
a. During pregnancy.
b. Due to blood loss.
c. Due to nutritional iron deficiency.
d. Due to poor absorption of iron from the gut

9. • Drug-Ferrous sulphate(orally)-200 mg TDS after food
• Prophylaxis of Iron therapy:- pregnancy and infancy(100 mg)
• Acute Iron Poisoning:-
• Common-young children (Accidental intake of iron tablets)
• Symptoms:-nausea, vomiting, epigastric pain, bloody diarrhea, dehydration,
cyanosis, drowsiness, hyperventilation, metabolic acidosis, convulsions, coma
and death.
• Unfortunately-Activated charcoal therapy doesn’t work here
• Rx-(Treatment)
A. General Supportive measures:-
A-Airways B-Breathing C-circulation
I.V.-Diazepam-to control convulsions.
Specific Therapy-I.V./I.M. Desferrioxamine (Antidote) a potent iron chelating
agent-promote excretion

10. • It’s a Complex cobalt-containing compound present in diet & synthesized by the
colonic bacteria
• Dietary source-
• Animal origin, such as meat, liver, egg, fish, cheese,
• Legumes(only vegetable source-due to presence of micro-organisms in nodules )
etc.
• Pharmacokinetics:-
• Absorption:-
• Site-distal ileum by specific transport system
Ingested Vit-B12 (Food soure)
↓↓
At stomach:- complexes with intrinsic factor Secreted by gastric
parietal cells
Vitamin B12

11. ↓↓
At terminal ileum vitamin B12–IF complex bind to specific receptor & absorbed in blood
↓↓
In blood-vitamin B12 is bound to transcobalamin-II &
transported to various cells of the body
↓↓
Liver-excess Vit-B12 Storage(3-5mg)
Excretion:-Bile and undergoes enterohepatic cycling
Deficiency-cause due to inadequate absorption
Physiological roles of Vit-B12-
Required for DNA synthesis
For integrity of nervous system
For normal haemopoiesis and for the maintenance of normal myelin.

12. • Preparation:-
• Cyanocobalamin (i.m. or s.c.),
• Hydroxocobalamin (i.m.)
• Methylcobalamin (oral)-active form
• Should never administered I.V. because of risk of anaphylaxis
• Deficiency of Vit-B12:-
• Manifested by-
• Pernicious Anemia, glossitis, mood change, hallucinations
• Neurological problems:-
• Bilateral peripheral neuropathy (loss of peripheral vision)
• Optic Atropy (retinal tissue destroyed)
• Dementia
• Degradation of Posterior & pyramidal tract of the spinal cord
Convert to active form

13. • Uses:-
• Pernicious anaemia:-
• Autoimmune destruction of the gastric parietal cells that synthesize intrinsic
factor (IF) leading to ↓intestinal absorption of Vit-B12
• Cause- deficiency of Intrinsic factor
• Rx-I.M.Vit-B12 preparation not oral preparation (Life time treatment)
• In megaloblastic anemia-Vit-B12+folic acid to avoid neurological abnormalities
• Trigeminal neuralgia, multiple sclerosis and other neuropathies-Oral
methylcobalamin
• Member of Vit-B complex group
• It’s a combination of glutamic acid, para-aminobenzoic acid and pteridine nucleus
Folic Acid

14. • Human do not synthesize folic acid
• Dietary source:- fresh green leafy vegetables, liver, yeast, kidney, fruits,
mushroom, milk etc.
• Daily requirement-100μg (Adult)
• ↑Requirement-500-600μg during pregnancy, lactation, disease condition
• Pharmacokinetics:-
• Dietary form of Folate–as polyglutamates (unabsorbable form)
• Polyglutamates monoglutamate (Absorbable form)
• Folate-itself is inactive, Active form- Tetra-hydrofolate
• Site of absorption-proximal part of the jejunum. (convert to Tetra-hydrofolate)
• Transport-active transport (large dose) & passive transport (small dose) through
blood in methyl tetrahydrofolate form
• Storage-liver (for 3-4 month)
intestinal enzyme folate conjugase

15. • Physiological function:-
• Required for DNA synthesis, purine synthesis
• Causes of folate deficiency:-
1. Dietary deficiency:- most common.
2. ↓absorption-malabsorption(disease of gut-coeliac disease)
3. Diminished storage (hepatic disease).
4. Decreased utilization (phenytoin, phenobarbitone)-enzyme inducer
5. ↑ demand (pregnancy, lactation, haemolytic anaemias).
6. Drug induced-
methotrexate, trimethoprim, pyrimethamine-inhibit enzyme DHFR
Manifestations of folate deficiency:-
Megaloblastic anaemia/macrocytic Anaemia
Neural tube defect in developing foetus-Spina bifida, Anencephaly

16. • Preparations:-
• Oral (tablet and liquid)-1-5mg and parenteral administration (combination with
other vitamins or iron)
• USES:-
1.Megaloblastic anaemia due to:-
• a. Nutritional folate deficiency.
• b. Increased demand (pregnancy, lactation).
Rx-Oral preparation of folic acid+Vit-B12
“Megaloblastic Anemia should not be treated folic acid alone”
2.Drug induced deficiency of folic acid-Folic acid low dose
3.Prophylactic therapy:- During pregnancy-starting from first trimester to prevent
neural tube defects.(0.5mgday)
4.Methotrexate toxicity: -is used to antagonize methotrexate toxicity
• SE:-oral preparation safe but injectable form cause hypersensitivity reaction

17. Fibrinolytic system involved in - inhibiting clot formation in blood by removal
of fibrin
Purpose of thrombolytic therapy:- rapid lysis of already formed clots in both
arteries + veins & re-established tissue perfusion
They are tissue plasminogen Activators (tPA)
MOA:-
Fibrinolytics (Thrombolytics)
rapidly dissolves the blood clot
 Activation of the
fibrinolytic system by
stimulating the conversion
of inactive plasminogen to
plasmin

18. • Drugs:- Streptokinase, Urokinase, Alteplase, Reteplase, Tenecteplase
• Individual drugs:-
Streptokinase:- It is a foreign protein derived from β-haemolytic streptococci
• It is-
• Antigenic-Stimulate the formation of Antibodies
• Pyrogenic-cause allergic reaction
• Destroyed by circulating Antistreptococcal antibodies
• MOA:-Streptokinase binds with circulating plasminogen to form a complex that
activates plasminogen to plasmin
• Administered- i.v. infusion
• Side Effect:-Bleeding, hypotension, allergic reactions like fever, chills, skin
rashes and rarely anaphylactoid reaction
Urokinase:-It is an enzyme isolated from human foetal kidney cell culture

19. • Have no Antigen activity
• Don’t cause allergic reactions
• Not destroyed by antibodies
• MOA:-It directly activates plasminogen to plasmin
• Side effect-Bleeding can occur hypotension and allergic reactions are rare
• Alteplase:- recombinant tissue plasminogen Activators (rtPA)
• MOA:-selectively activates plasminogen that is bound to fibrin and avoids the
activation of circulating plasminogen
Specific feature:-
Nonantigenic, Nonpyrogenic, Not destroyed by antibodies, Rapid acting, More
potent, More effective, More expensive
• Tenecteplase:- (longest acting)
• Recombinant form of tPA

20. • Advantage:-
Faster action
More effective
Safer,
Easier to administered-the entire dose is delivered over a single 5-sec bolus
no infusion or second bolus is necessary
• Uses of fibrinolytics:-
1. Acute MI(STEMI):- restore coronary artery patency by promoting the
conversion of plasminogen to plasmin & dissolve the clot
Therapy more effective- administered i.v. within first 6h of onset of symptoms
2. Deep vein thrombosis: Thrombolytic therapy helps to prevent pulmonary
embolism.
3. Pulmonary embolism:- Fibrinolytics are used to lyse the clot.

21. • Contraindications:-
• Surgery within 10 days
• Serious G.I. bleeding within 3 months
• History of hypertension (diastolic pressure > 110 mm Hg)
• Active bleeding or haemorrhagic disorder
• Previous cerebrovascular accident or active intracranial process
• Aortic dissection
• Acute pericarditis
• PCI within last 6 months
• Side effect:-
• Bleeding
Rx by Discontinuation of drug
Administration of fresh frozen plasma(containing of fibrinogen & clotting factors)
Administered-Antagonist of fibrinolytic agents like Tranexamic acid

22. • Allergic reaction such as serum sickness (Streptokinase)
• Antifibrinolytics block the conversion of plasminogen to plasmin and thus inhibit
fibrinolytic activity
• Epsilon amino-caproic acid (EACA):-
• Administered-orally/intravenously.
• It is used mainly to control bleeding due to overdose of Fibrinolytics after tooth
extraction and surgery in haemophiliacs.
• It can also be used in hematuria and bleeding following obstetric complications.
• It rarely causes myopathy and muscle necrosis.
• Tranexamic acid:-
• More potent than EACA
• Available-oral, i.v. and topical administration
Anti-fibrinolytics

23. • USES:- to control bleeding due to excessive fibrinolytic activity and following
tooth extraction, tonsillectomy, prostatectomy, etc.
• Dental use:-
• Haemophiliacs pt.
• Pt. on anticoagulant therapy
• SE:- nausea, vomiting, diarrhoea, headache, etc.
Tranexamic acid
soaked gauze or
mouthwash
↓ bleeding
postoperatively

24. ANTIPLATELET DRUGS
• Drugs that inhibit platelet aggregation are called antiplatelet drugs
• Under normal hemostasis:-
• Platelets→ prevent Hemorrhage (internal bleeding)maintain vascular integrity
• Haemostasis:-Arrest of Bleeding.
• Hemostasis is achieved by
(1) vascular constriction
(2) formation of a platelet plug
(3) formation of a blood clot
Platelet function
disruption of endothelium
platelet adhesion
platelet activation
Platelet release
Platelet aggregation
agonist binding
• Thrombin
• Serotonin
• ADP
• TXA2

25. Platelet adhesion and aggregation Platelet activation

30. Hemostasis (platelets):-
Vessel damage
(injury to endothelial cell wall)

Vasospasm
(vessel constriction)

Platelet adhesion
(platelets bind to damaged vessel via GP Ia, which binds to collagen,
and GP Ib, which binds von Willebrand factor)

Platelet activation- release of various mediators

Platelet aggregation
(platelets bind to themselves via GP IIb/IIIa, which also binds
fibrinogen and other macromolecules)

Temporary hemostasis
Endothelin

32. • Any Vascular damage such as rupture of an atherosclerotic plaque result in platelet
dependent thrombus that leading to vascular occlusion(blocked)
Result-Hypoxia & infraction of distal tissue
Therefore
Thrombotic blocked of coronary artery
Result in MI
Thrombotic blocked of cerebral artery
Result in Ischemic stroke
Because of this central role of platelet in arterial thrombosis-Anti-platelet
therapy is beneficial
Need of Anti-platelet therapy

33. ANTIPLATELET
DRUGS
Thromboxane
(TXA2) synthesis
inhibitor
Glycoprotein (GP)-
IIb/IIIa-receptor
antagonists
Thienopyridine
derivatives
Phosphodiesterase
inhibitor
 Low-dose aspirin • Abciximab,
• Eptifibatide
• Tirofiban.
• Ticlopidine
• clopidogrel
• Dipyridamole.
Aspirin (TXA2 synthesis inhibitor):-
o Low-dose aspirin (75–325 mg) irreversibly acetylates platelet COX-I and reduces the
production of TXA2
o The antiplatelet effect lasts for the life-time of the platelets, i.e. 7–10 days
o Aspirin-higher dose (2-3gm/day)-inhibit Thromboxane A2+PGI2 hence beneficial effect of
PGI2 is lost
o Side effect-GI irritation, bleeding ,allergic reaction
o Uses:-prevention of thrombotic events in pt. with coronary & cerebrovascular artherosclerosis
o Contraindication:- Gastric ulcer, Allergic to aspirin

34. Dipyridamole (phosphodiesterase inhibitor):-
It is a vasodilator.
MOA:- Dipyridamole
↓↓
Inhibits phosphodiesterase & adenosine uptake
↓↓
↑cAMP levels
↓↓
↓intracellular Ca++
(Inhibit Platelet activation→ inhibits platelet aggregation)
USES:-
 Dipyridamole + warfarin→ prevent embolism during PO period in patients with
prosthetic heart valves
 Dipyridamole + Aspirin→ Prevent thrombosis in patients with thrombotic
disease
 SE:-GI-complaints, Headache facial flushing, dizziness & hypotension

35. • Thienopyridine derivatives(ADP-Receptor blocker):-
• Drugs:- Ticlopidine , clopidogrel
• MOA:-Interferes with ADP-induced binding of fibrinogen to platelet membrane at
specific receptor sites
• Resulted-Inhibits platelet adhesion and platelet-platelet interactions
• They are Prodrugs→ converted to an active metabolite in liver
• Ticlopidine:-
• Well absorbed orally (>80%)
• Long duration of antiplatelet effect
• USES:-
Thromboembolic stroke:- As alternative to aspirin to prevent recurrence
MI prophylaxis
• Side effect:- Nausea, vomiting, diarrhoea, leucopenia, agranulocytosis,
thrombocytopenia and GI bleeding

36. Clopidogrel:-
Congener of ticlopidine-similar mechanism of action
It is also given orally
But has a lower incidence of adverse effect like cutaneous, gastrointestinal, or
hematologic reactions than ticlopidine
Usually clopidogrel is preferred over ticlopidine
Except-Drug interaction occur then Ticlopidine preferred over clopidogrel
Drugs:-Abciximab, Eptifibatide, Tirofiban
MOA:-They block GP IIb/IIIa receptors for fibrinogen and von Willebrand’s
factor on platelet surface & inhibit the final step in the process of platelet
aggregation
Glycoprotein (GP)-IIb/IIIa-receptor antagonists

37. • Administered-parenterally
• Side effect-Bleeding
• It is a Expensive drug-As monoclonal drugs
• Uses:-
1. Acute MI:- Low-dose aspirin is most commonly used in high-risk individuals
to reduce the incidence of MI and in post-MI patients to prevent recurrent attacks.
2.Coronary angioplasty:-
Given I.V. to high-risk patients
Stent placement often with clopidogrel