DRUGS ACTING ON BLOOD

(Summary)1

Assoc. Prof. Ivan Lambev (www.medpharm-sofia.eu)

I. HAEMATOPOETIC DRUGS

Haematinics are the agents required in the formation of blood, and are used for the treatment of anaemias.
Anaemias occur when the balance between production and destruction of red blood cells is disturbed by:
 blood loss (acute or chronic);
 impaired blood red cells formation due to deficiency of iron, cyanocobalamin, folic acid or erythropoetin
or due to bone marrow depression (hypoplastic anaemia);
 increased destruction of erythrocytes (haemolytic anaemia).
 The total body iron is about 3.5–4 g in man and 2.5 g in woman, 70% of which circulate in the blood as
haemoglobin. About 15 to 18% is stored in the liver, spleen and bone marrow chiefly as ferritin and
haemosiderin. Maximum iron absorption by active transport occurs in the duodenum and proximal
jejunum. Ascorbic acid and SH– group containing amino acids (present in gastric juice) facilitate the
conversion of Fe3+ in Fe2+ and promote its absorption. Iron absorption is hindered by coffee, tea, antacid
agents, phosphates (rich in egg yolks), tetracyclines. In the body iron is distributed into:
 Haemoglobin (Hb) – 66%
 Iron storages (ferritin and haemosiderin – 25%
 Myoglobin in muscles – 3%
 Parenchimal iron (as prostetic group in cytochrome, peroxidases, catalases, xanthine oxidases and
other cellular enzymes) – 6%.
Haemoglobin is a protoporphyrin and each molecule has 4 iron-haeme residues. It has 0.33% iron. Thus loss
of 100 ml of blood (containing 15 g Hb) means loss of 50 mg elemental iron. For full haemopoetic effects in adults
a total of 200 mg of elemental iron should be administered daily, divided in 2 or 3 doses after meals or in between
them. For prophylactic use 30 mg of elemental iron daily is sufficient. The so called mucosal block is a
mechanism that prevents the entry of excess iron in the body.

 Iron Compounds [used to treat microcytic hypochromic (iron deficiency) anaemia]

ADRs: Constipation, diarrhoea (rarely), epigastric pain, heart burns, nausea, vomiting, metallic taste, and
staining of teeth (mainly with oral liquid or chewable preparation). Acute iron toxicity occurs mostly in young
children. Unfortunately, activated charcoal, does not work here. Desferoxamine, an iron chelator, is a specific
antidote that is given systematically to remove iron.
a) Oral Preparations (Fe2+)

Aspartate salts: Ferrospartin (tabl. 350 mg, containing 50 mg Fe2+)

Glutamate salts: Glubifer

Sulfate salts: Ferro-gradumet, Hemofer prolongatum (film-coated tablets 325 mg, containing 105 mg
Fe2+: 2 x 1 tablet daily after the meal), Tardyferon depot (one tablet contains 80 mg Fe2+ which is
included in mucoprotein, obtained by the intestinal mucosa of sheep; thus the absorption continues 7 h)

Fumarate salts: Sorbifer duroles
b) Intravenous Preparations (Fe3+): Cosmofer, Diafer, Ferinject, Idafer, Monofer
Local ADRs: Pain at the site of action, skin pigmentation, sterile abscess.
Systemic ADRs: Fever, headache, joint pain, urticaria, lymphadenopathia; anaphylactoid reaction (palpitation,
chest pain, dyspnoea, cardiovascular collapse) may occur with iron-sorbitol prepartions but rarely with other
preparations). To avoid any risk of hypersensitivity reaction it is always safe to perform a sensitivity test with a
small dose before administering a full i.m. or i.v. dose of parenteral iron preparation.

 Vitamins, used to treat megaloblastic anaemia

1
Adapted (2015) from: Sharma HL and Sharma KK. Principle of Pharmacology, Paras Medical Publisher, Delhi (2007);
Tripathi KD. Essentials of Medical Pharmacology. 6st Edition. Jaypee Brothers. New Delhi (2008) and www.bda.bg
 Cyanocobalamin (vitamin B12 – amp. 250 mcg/1 ml i.m.). Cyanocobalamin and hydroxocobalamin are
complex cobalt-containing compound present in diet (liver, kidney, sea fish, egg yolk, meat, cheese) and
referred to as vitamin B12. Vitamin B12 is linked with folate metabolism. Megaloblastic anaemia occurring due
to deficiency of either is indistinguishable. Vitamin B12 is essential for the conversion of homocysteine to
methionine. Methionine is needed as a methyl group donor in many metabolic reaction and for protein
synthesis, as well as for the synthesis of phospholipids and myelin. Vitamin B 12 is essential for cell growth and
multiplication.
Manifestations of vitamin B12 deficiency are: megaloblastic anaemia, glossitis, peripheral neuritis,
paresthesias, poor memory, mood changes, hallucinations.
Indications of vitamin B12: treatment of its deficiency, treatment of megaloblastic anaemia, tobacco amblyopia.
Mega doses of vitamin B12 have been used in neuropathies and psychiatric disorders as a general tonic to
allay fatigue.
Hydroxocobalamin is highly protein-bound and longer acting, but is associated with the development of
antibodies (hence lesser in use).
Folic acid. Humans do not synthesize folic acid and meet theirs requirements from green leafy vegetables,
fruit, mushrooms, liver, meat, kidney, eggs, milk and yeast. In the intestinal mucosa of jejunum folic acid is
reduced by dihydrofolate reductase to tetrahydrofolic acid. Tetrahydrofolic acid through 1-C carbon transfer
reactions is involved in the synthesis of purines and pyrimidines which are essential for DNA synthesis.
Deficiency of folic acid leads to megaloblastic anaemia and teratogenic effects (spina bifida etc.). Vitamin B9
prophylactically can be used during pregnancy and lactation – 0.4 mg p.o. daily)

 Haematopoetic Growth Factors

a) Erythropoetin: Epoetin alfa and Epoetin beta (Recormon). Erythropoietin stimulates erythrocyte
proliferation and differentiation by acting on specific receptors present on red cell progenitors and promotes
the release of reticulocytes. It is used to treat anaemia in chronic kidney failure, anaemia resulting from
anticancer chemotherapy or AIDS.
b) Myeloid Growth Factors (Colony Stimulating Factors – CSFs)
Granulocyte (G) and Granulocyte-Macrophages (GM) CSFs are cytokines. They accelerate the formation of
matured leucocytes by acting on many progenitor cells.
Filgrastim (recombinant G-CSF), Lenograstim (rG-CSF), Molgramostim (rGM-CSF) and Sargramostim (rGM-
CSF) are used: to reduce the severity and duration of neutropenia induced by anticancer drugs, radiotherapy
or following bone marrow transplant; to treat congenital neutropenia, cyclic neutropenia and neutropenia
associated with aplastic anaemia.
c) Megakaryocythe Growth Factors: Oprelvekin (IL-11) and Thrombopoietin, used to treat thrombocytopenia
following anticancer chemotherapy.

II. ANTIHAEMORRHAGIC DRUGS (HAEMOSTATICS)

 Coagulants
a) Local Haemostatics
 Sterile, gelatin-base haemostatic sponges: Gelaspon® (applied topically as an adjunct to haemostasis
when the control of bleeding by conventional procedures is ineffective to reduce capillary ooze or is
impractical)
 Sterile, collagen-base haemostatic sponges: Tachocomb® (a local haemostatic agent; composed of
fibrinogen, thrombin, and aprotinin integrated into the surface of a collagen fleece)
 Fibrin Sealants (obtained from human plasma) are used in dental procedures
 Vasoconstrictors for temporary haemostasis: to stop epistaxis by packing a cotton gauze with 1%
Epinephrine or 0.5% Oxymetazoline
 Miscellaneous: Solutio Hydrogenii peroxydi diluta 3% (Solution of Hydrogen Peroxide 3%)
b) Systemic Coagulants
 Calcium salts (Ca2+ – clotting factor IV): Calcium chloride (i.v.), Calcium gluconate
 Vitamin K: Phytomenadionе (vitamin K1 is fat-soluble, obtained from leafy vegetables), Menaquinone
(vitamin K2) is synthesised by intestinal bacterial flora), Menadionе (vitamin K3 is a synthetic analogue).

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 Vitamin K is required for the synthesis of four clotting factors from the liver cells: II (prothrombin), VII
(proconvertin), IX (Cristmas factor) and X (Stuart factor).
 Indications of phytomenadion: prolonged antibiotic use; overdose of oral anticoagulants; newborns of or
premature infants (because they have low level of prothrombin and other clotting factors); malabsorption
syndrome/obstructive jaundice; liver diseases (cirrhosis, viral hepatitis).

 Coagulating (Clotting) Factors

a) For treatment of Haemophilia- A or B: Blood coagulation factor VII (Pronconvertin)
b) For treatment of Haemophilia-A: Blood coagulation factor VIII (Antihaemophilic factor-A)
c) For treatment of Haemophilia-B: Blood coagulation factor IX (Antihaemophilic factor-B)
d) For prophilaxis or treatment of haemorrhagic diathesis in hypo- or afibrinogenemia: Fibrinogen (clotting
factor I)

 Antifibrinolytics
Mechanism of action: The aminoacid agents competitively inhibit activation of plasminogen to plasmin and
inhibit fibrinolysis. Aprotinin inhibits plasmin, kallikrein and platelet activation.
ADRs: Unwanted deep vein thrombosis.
a) Aminoacids: Aminomethylbenzoic acid, Aminocapronic acid, Tranexamic acid. The aminoacid agents are
used in haemophilic patients who may be prone to bleeding, after surgery, as the wound is healing.
b) Protease inhibitors: Aprotinin is used in hyperplasminaemia caused by fibrinolytic drugs overdose and also
to prevent blood loss during cardiac bypass surgery.

 Analogues of Vasopressin: Felipressin (in dental practice), Terlipressin (in acute esophageal variceal
haemorrhage)

 Angioprotectors (Vasoprotectors)
a) Capillarotonic drugs
Bioflavanoids: Peflavit C, Rutin (a plant glycoside which is being used to prevent capillary bleeding with
vitamin C)
Synthetic agents: Doxium (used in retinopathy); Ethamsylate increases capillary wall stability by exerting
anti-hyaluronidase activity and also by inhibition of PGI2 synthesis and promoting platelet aggregation. It is
used to prevent bleeding in postpartum haemorrhage, menorrhagia and tooth extraction.
b) Venotonic drugs: Detralex, Endotelon, Troxevasin (semi-synthetic agents)

III. ANTITHROMBOTIC DRUGS

 Antiplatelet Drugs
Indications: Myocardial infarction (Low doses of aspirin or aspirin/clopidogrel are used to reduce mortality and
to prevent reinfarction); unstable angina (aspirn/clopidogrel), coronary bypass implants (antiplatelet agents
are used to maintain the patency of implanted bypass vessel); prosthetic heart valves and arterio-venous
shunts; venous thromboembolism and peripheral vascular disease; cerebrovascular transient ischaemic
attacks (aspirin/clopidogrel or aspirin/dipyridamole).
a) Irreversible inhibitors of platelet COX-1, which prevent TxA 2 production: Aspirin Protect® (100 mg/24 h),
Indobufen
b) Platelet ADP inhibitors (tienopyridines): Clopidogrel, Prasugrel, Ticlopidine
c) Inhibitors of GP IIb/IIIa fibrinogen receptors (disintegrins): Abciximab, Eptifibatide, Tirofiban (i.v. infusion
with heparin)
d) Analogues of PGs: Alprostadil (PGE1), Iloprost (PGI2)
e) Inhibitors of Phosphodiesterase: Dipyridamole

 Anticoagulants
Indications: Anticoagulants reduce blood clotting which can help prevent deep vein thrombosis, pulmonary
embolism, myocardial infarction and ischemic stroke.
A. Parenteral anticoagulants

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 a) Group of Heparin (indirect thrombin inhibitors)
▼Low molecular weight heparins (s.c. application): Enoxaparin, Nadroparin (Fraxiparine), Parnaparin etc.,
incuding synthetic low molecular weight heparins (Fondaparinux − s.c.)
▼Sodium salts of Heparin (i.v. infusion or s.c. application).
Mechanism of action: Antithrombin III (AT-III) plays a crucial role in natural endogenous anticoagulant
mechanisms by blocking the activity of activated clotting factors XII (Hageman factor or contact factor), XI
(Plasma thrombopastin antecedent), X (Stuart factor or thrombokinase), IX (Christmas factor) and II
(thrombin). Heparin accelerates AT-III activity 1000 folds especially against clotting factors IIa and Xa, but low
molecular weight heparins accelerate AT-III activity only against clotting factors Xa (thrombin is not).
Indications: Prevention and treatment of deep vein thrombosis and pulmonary embolism, myocardial
infarction, unstable angina, during cardiac bypass surgery and in placing artificial heart valves to prevent
formation of any thrombus/emboli; to prevent clotting in extracorporeal circulation (e.g. during haemodialysis);
for anticoagulation during pregnancy (In contrast to coumarins heparin does not cross placenta and is not
associated with foetal malformation).
ADRs: Heparin-induced thrombocytopenia, osteoporosis, spontaneous fractures on prolong use, transient
alopecia, hypersensitivity; GIT bleeding, haematuria. Antidote: Protamine sulfate
Local Heparin containing drugs: Lioton (1000 UI heparin/g gel) − per cutaneum
b) Prepararations of antithrombin: Antithrombin III
c) Direct thrombin inhibitors (used in heparin-induced thrombocytopenia): Argatroban, Bivalirudin (synthetic
analogue of Hirudin), Hirudin (peptide in the saliva glands of Hirudo medicinalis), Lepirudin (r-Hirudine)
B. Oral anticoagulants
a) Oral indirect-acting anticoagulants (Vitamin K antagonists)
▼Coumarin derivatives
Mechanism of action: These drugs competitively inhibit vitamin-K reductase, resp. synthesis of clotting factors
II (prothrombin, resp. thrombin), IX (Christmas factor or plasma thromboplastin component or antihaemophilic
factor-B) and X (Stuart factor or thrombokinase) by the liver. The anticoagulant effect develops within 1–3
days.
Antidote: Phytomenadione (vitamin K1). Fresh frozen plasma or factor IX concentrate , which contains large
amounts of prothrombin complex, can also be i.v. infused.
Acenocoumarol (Sintrom – t1/2 8–11 h)
Warfarin (t1/2 40 h). The oral bioavailability of warfarin is 100%. Over 99% of warfarin and acenocoumarol are
bound to plasma proteins which results in their low Vd. It is a reason for unwanted drug interactions (incl.
displase of plasma proteins from co-trimoxazole, aspirin, indometacin, phenytoin, probenecid).
Indications: Prevention and treatment of deep vein thrombosis and pulmonary embolism, myocardial
infarction, unstable angina, after placing artificial heart valves, persistent forms of atrial fibrillation.
ADRs: transient alopecia, dermatitis, diarrhoea, teratogenity (Coumarin derivatives cross the placenta and can
lead to haemorrhagic disorders in the foetus, foetal bone deformities); GIT bleeding, haematuria
International Normalized Ratio (INR): 2–4.
▼Indandiones: Phenindione (ATC: B01AA02)
b) Oral direct-acting anticoagulants (used for the prevention of venous thromboembolism in adult patients
undergoing elective hip or knee replacement surgery). They does not require frequent blood tests for
international normalized ratio monitoring, while offering similar results in terms of efficacy.
 Direct factor Ха inhibitors: Apixaban, Rivaroxaban
 Direct thrombin inhibitors: Dabigatran (Pradaxa®). It offers an alternative to warfarin as the preferred
orally administered anticoagulant ("blood thinner"), including to prevent strokes in those with atrial fibrillation
due to causes other than heart valve disease, and at least one additional risk factor for stroke (congestive
heart failure, hypertension, age, diabetes, and prior stroke)

 Fibrinolytics
Mechanism of action: Fibrinolytics block activiation of plasminogen to plasmin, which in turn dissolves the
fibrin network as the wound gets healed. As compared to arterial thrombi, venous thrombi are lysed more
easily, and recent thrombi are lysed better than older ones.
Indications: Fibrinolytics used to treat acute myocardial infarction, peripheral arterial thrombosis/embolism and
for unclotting catheters and shunts.

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ADRs: Haemorrhage is the major side effect of this drugs. As a result, an unsuspected peptic ulcer may bleed
following their use. Unfortunately, increased availability of a local thrombus at the site of fibrin clot, may
enhance rethrombosis after the lysis of the initial clot. The allergenicity to Streptokinase is the highest.
Alteplase (Tissue Plasminogen Actiavator – t-PA) is now prepared by recombinant DNA technology using
human tissue culture. However, alteplase has short t1/2 (5–10 min) and shows high incidence of reocclusion,
thus necessitating concomitant use of i.v. Heparin also. It is expensive.
Reteplase is also a recombinant tissue plasminogen activator, but it has a longer t1/2 (15–20 min).
Streptokinase is a protease enzyme, obtained from beta-haemolytic streptococci. It has t1/2 1 h. As a foreign
protein, hypersensitivity reactions (rashes, fever, hypotension) are frequent (about 3%). Prior presence of
antistreptococcal antibody may reduce its efficacy and it cannot be repeated within one year. However, it is
the least expensive.
Tenecteplase is a genetically engineered mutant from alteplase, but with a longer t1/2 (2 h). It is given as a
single bolus injection over 5 sec. It is very expensive!
Urokinase is a protease enzyme which is now produced from cultured human kidney cells. It is nonallergenic,
nonpyrogenic and does not produce hypotension (unlike streptokinase).