Pharmacology of the blood

ANTICOAGULANT, ANTITHROMBOTIC AND ANTI-PLATELET DRUGS.

DRUGS USED IN ANEMIA

Definitions
Hemostasis: is the arrest of blood loss from damaged Blood vessels by: 1.Platelet activation, adhesion and aggregation 2.Blood coagulation fibrin formation.

Thrombosis: pathological condition results from formation of haemostatic plug within the vasculature in the absence of bleeding. The thrombus can break away , forming embolus that may lodge downstream causing ischemia and infarction.

 Anticoagulants: Drugs that inhibit the development and propagation of thrombus. Antiplatelets: Drugs that inhibit platelet functions activation, adhesion and aggregation.
Thrombolytics (Fibrinolytics): Drugs that promote removing the products of coagulation.( fibrin removal)

Blood Coagulation (fibrin formation)

The coagulation process that generates thrombin consists of two interrelated pathways: the extrinsic and the intrinsic systems.
Both systems involve a cascade of enzyme reactions that sequentially transform various plasma factors (proenzymes) to their active (enzymatic) forms.

 They ultimately produce Factor Xa, which converts prothrombin (Factor II) to thrombin (Factor IIa). Thrombin plays a key role in coagulation, because it is responsible for generation of fibrin, that forms the mesh-like matrix of the blood clot

Anticoagulants
Heparin Large sulfated polysaccharide polymer Not absorbed orally, Given IV or SC, not IM Hematomas. Onset immediate after IV, and needs 60 min after SC. It is active in vivo & in vitro

MOA: Bind to Antithrombin III this complex combines with & inactivates thrombin(IIa) & other factors, especially factor X Antithrombin III : an endogenous anticlotting protein that irreversibly inactivates thrombin & factor X, its enzymatic action that is accelerated by Heparin

Unfractionated Heparin
AT
Clotting Factor

AT

Clotting Factor

In the presence of heparin, antithrombin III proteolyzes thrombin & factor Xa approximately 1000-fold faster than in its absence.

Heparin

Uses
1. 2. 3. 4. Deep Venous Thrombosis (DVT) Acute MI Pulmonary Embolism Used prophylactically to prevent postoperative venous thrombosis 5. Drug of choice for treating pregnant women with thromboembolic disorders (because it doesnt cross the placenta) 6. Prosthetic heart valve

 Anticoagulation effect of Heparin is monitored by measurement of activated partial thromboplastin time (aPTT) is 1.5- to 2.5-fold that of the normal control.

Adverse effects
1. Bleeding from any site. TREATMENT: stop the drug. and antidote may be needed. Protamine sulphate strong +ve charged base, slow IV injection, Fresh blood may be useful.

2. Thrombocytopenia 3. Osteoporosis with chronic treatment

Low molecular weight heparin (LMWH)

Derived from UFH by chemical / enzymatic depolymerisation Reduced activity against thrombin relative to factor Xa.

Heparin & LMWH-mediated inactivation of thrombin & factor Xa

(LMWH)
Example: Enoxaparin Longer plasma half life-dosing is less frequent 1-2 x / day. Given SC. more bioavailability. Less thrombocytopenia Less bone loss.

LMWH
More predictable anticoagulant response than UFH Monitoring -Not regularly monitored No antidote.

Oral anticoagulants
Example: warfarin Structurally related to vitamin K Narrow therapeutic window Delayed onset 8 - 12 hrs Overdose - reversed by vitamin K infusion Can cross placenta - do not use during pregnancyteratogenicity Active in vivo only. Metabolized by hepatic microsomal enzymes.

MOA:
Normally, vitamin K is converted to vitamin K epoxide in the liver. This epoxide is then reduced by the enzyme epoxide reductase. The reduced form of vitamin K epoxide is necessary for the synthesis of many coagulation factors (II, VII, IX and X)

 Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting coagulation. 4872 hrs are needed for full effect (?).

Therapeutic uses:
Warfarin is used to prevent the progression or recurrence of acute deep-vein thrombosis or pulmonary embolism after initial heparin treatment. It is also used for the prevention of venous thromboembolism during orthopaedic or gynecologic surgery. Prophylactically, it is used in patients with myocardial infarction, prosthetic heart valves, or chronic atrial fibrillation.

 Anticoagulation is monitored by Prothrombin time (PT) that should be measured daily & the dose adjusted until INR is stabilized Patient Thrombin Time INR: Normal Prothrombin Time INR: International normalized ratio (should be between 2-3.5)

Adverse effects
Bleeding from any site. treatment: stop the drug, fresh blood and the specific antidote Phytomenadione (vitamin k)

Drug interaction- with Warfarin

Category Mechanism Representative Drugs

Drugs that Increase Warfarin Activity

Decrease binding to Albumin

Aspirin

Inhibit Degradation

Cimetidine,

Drug interaction with Warfarin

Drugs that promote bleeding
Inhibition of platelets Aspirin

Inhibition of clotting Factors

Induction of metabolizing Enzymes

heparin

Drugs that decrease Warfarin activity

Barbiturates Phenytoin

Contraindications of Anticoagulants
1. Bleeding tendencies. 2. Ulcerative lesions of the GIT. 3. Suspected intracranial hemorrhage. 4. Severe hypertension. 5. Advanced hepatic and renal disease.

Antiplatelet drugs
Example: Aspirin Prevents platelet aggregation /adhesion.

Aspirin irreversibly acetylating COX-1.

COX-1 is responsible for the production of thromboxane A2, a potent vasoconstrictor and stimulator of platelet aggregation

MOA of aspirin

 TXA2 synthesis does not recover until the affected platelets are replaced in 7-10 days. Low doses inhibit platelet TXA2 more than endothelial PGI2. Clinical use - prevents arterial thrombus Myocardial infarction (MI), stroke

Antiplatelet Drugs Main adverse effects of antiplatelet drugs is BLEEDING.

Fibrinolytic (thrombolytic) agents

Enhance degradation of clots Activation of endogenous protease Plasminogen (inactive form) is converted to Plasmin (active form) Plasmin breaks

down fibrin clots

MOA of fibrinolytic agents

Fibrinolysis
Exogenously administered drugs
Streptokinase - bacterial product
continuous use - immune reaction

Tissue plasminogen activator (tPA) alteplase genetically cloned

no immune reaction EXPENSIVE

Fibrinolytic Drugs
Clinical uses: The main use is in MI, with in 12 hrs of onset of MI, the earlier the better.

Other uses is in: Acute thrombotic stroke, with 3 hrs of the onset of stroke.

Fibrinolytic Drugs
ADRs: Bleeding .if serious, treated by Tranexamic acid or fresh plasma Streptokinase may cause allergy.

Antifibrinolytic Drugs
Tranexamic acid: Inhibits plasminogen activation and thus inhibits fibrinolysis. Used to treat bleeding or risk of bleeding in: 1. Dental extraction. 2. Epistaxisis. 3. Menorrhagia. 4. Following fibrinolytic over dose.

Drugs used in anemias

Anemia is present when there is a decrease in the level of Hb in the blood below the reference range for the age and sex of the individual. This leads to decrease in O2 carrying capacity of Hb.

 Clinical features: Symptoms depend on the severity & speed of onset of anemia. Non-specific symptoms: fatigue, breathlessness, pallor, & palpitations

Based on size of RBCs

Microcytic anemia:
Iron deficiency anemia

Macrocytic anemia:
Megaloblastic anemia

Normocytic anemia:
Anemia of chronic disease

IRON DEFICIENCY ANEMIA Results in a production of Hb, with a small, pale RBC Iron supply is insufficient to maintain normal levels of Hb.

Epidemiology: Common in children from 6 months to 2 years, and teenage boys/girls. Common cause of anemia in developing countries

 Iron is necessary for oxygen transport by Hb.

Iron is supplied by diet, absorbed in the GI tract (duodenum).

Intestinal mucosa regulates iron absorption, influenced by iron body stores.

Iron is absorbed via cell surface receptors. Some of the iron passes through the cell and is carried in the blood by transferrin.

 Excess iron is stored as ferritin in the liver, spleen, BM, and muscle. Dietary iron is mainly as heme (Fe+2) which is easily absorbed. Non- heme iron in food is mainly (Fe+3) which needs reduction by HCl or vitamin C to (Fe+2) for absorption.

Pathophysiology:
Initially iron stores are depleted but the RBC are normal When all iron stores decrease, Hb synthesis decrease gradual fall of RBC production in bone marrow new RBC are smaller and paller decrease tissue oxygenation.

Causes:

1.Dietary deficiency Vegetarians, Malabsorption 2. Chronic blood loss Menorrhagia 3. Increased demand Pregnancy. 4. Inadequate absorption- Gastrectomy.

Clinical Presentation
Pallor of skin Irritability, fatigue, lethargy, tachycardia, Check anemia on conjunctiva, nail beds. Dyspnea, dizziness, SOB, headache, hypotension

koilonychia : Spooning of the fingernails occurs in children with severe iron deficiency anemia. It refers to abnormally thin nails which have lost their convexity, becoming flat or even concave in shape.

Treatment of Iron deficiency anemia

Consists of: 1.Correction of the underlying cause. 2. Iron replacement therapy. Which should be continued for 3 months Iron preparations: Oral Parentral

Oral Iron Preparations Ferrous sulphate tablets, 200 mg ferrous sulphate 3x/day for 1-2 weeks can increase Hb conc. By 1gm/dl. Ferrous gluconate tablets, Ferrous fumarate syrup. S/E: nausea, abdominal discomfort, constipation, black stools. Continue until Hb is normal& for at least 3 months,to replenish stores.

 Failure to respond to oral iron preparation: 1.Noncompliance (due to S/Es: Nausea, Vomiting, GI irritation) 2.Continued blood loss 3. Malabsorption Iron parentral preparation can be used when: 1.Intolerance to oral preparation 2. Rapid response is required 3.Iron can not be absorbed from GIT

parentral iron preparation

Iron given I.Me.g. Iron Sorbitol Citrate

Before injecting iron, oral iron should be stopped for at least 72 hours S/Es: Staining of the skin after I.M.

Megaloblastic anemia-general
Results from block of synthesis of nucleotide precursors of DNA
Maturation of cell nucleus is arrested, maturation of cytoplasm continues

Most common causes:

Vitamin B12 (Cobalamin) deficiency, more common Folate deficiency

B12 Deficiency
Most common cause: Pernicious anemia due to deficiency of Intrinsic factor Less common cause: Dietary: Less meat and vegans.

 B12 absorbed from animal protein in the diet Absorbed in the terminal ileum bound to intrinsic factor, a protein secreted by gastric parietal cells
Transported by transcobalamin II and stored in the liver. B12 stored in the liver 3 years supply Dietary B12 deficiency is rare Vegans diet

B12 deficiency anemia-general

Megaloblastic anemia symptoms

Yellowish of skin
pallor and jaundice

Mucosal changes
glossitis, anorexia, diarrhea,

B12 deficiency leads to complex neurologic syndrome:

paresthesias - early difficulty with balance - late

A smooth, beefy red tongue may be observed in the physical examination of a patient with vitamin B12 deficiency.

Treatment:
B12 (Cobalamin) which is given orally if there is no absorption problems Parenterally I.M. (Hydroxycobalamin, Cyanocobalamin).

Treatment of B12 deficiency anemia (1.0 mg) are given twice weekly for 3 weeks to replenish the body stores, then 1.0 mg monthly as a maintenance dose.

 Megaloblastic anemia due to B12 or FA deficiency are hematologically indistinguishable. Treatment of B12 deficiency with Folic acid alone may improve the hematological picture but do not improve and may worsen the neurological picture.

Folic acid
Folic acid is found in green vegetables Absorbed in the upper small intestine. Daily adult need: 200 g , increased in pregnancy. FA to be active it should be activated to FH4 which is maintained by dihydrofolate (DHF) reductase

FH4 is essential in DNA synthesis as a cofactor in purines and pyrimidines synthesis

Causes of folate deficiency: Poor intake-old age, alcohol excess. Malabsorption. Excess utilization-pregnancy. Drugs-phenytoin.

1. 2. 3. 4.

 Treatment 1.The underlying cause must be treated. 2.Oral folic acid 5mg daily for 4months. Prophylactically in individual at hazards from developing folate deficiency as: Pregnant women. Chronic hemolytic anemia. Prevention of spina bifida (neuronal tube defect).