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PHARMACOLOGYPHARMACOLOGYTeresita Lambo Quisumbing, Teresita Lambo Quisumbing,

MD,MMedSc, FPSPMD,MMedSc, FPSP

UV-Gullas College of MedicineUV-Gullas College of Medicine

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DRUGS ACTING ON BLOOD AND BLOOD FORMING DRUGS ACTING ON BLOOD AND BLOOD FORMING ORGANSORGANS

I. HEMATOPOIETIC AGENTSI. HEMATOPOIETIC AGENTS

A. Hematopoietic Growth FactorsA. Hematopoietic Growth Factors 1. Erythropoietin1. Erythropoietin 2. Myeloid Growth Factors2. Myeloid Growth Factors

2.1 Interleukin-3 (Il-3 or Multi-CSF)2.1 Interleukin-3 (Il-3 or Multi-CSF) 2.2 GM-CSF2.2 GM-CSF 2.3 G-CSF2.3 G-CSF 2.4 Colony Stimulating Factor (CSF-1 or M-CSF)2.4 Colony Stimulating Factor (CSF-1 or M-CSF) 2.5 Thrombopoeitin2.5 Thrombopoeitin

B. Agents Effective in Specific AnemiasB. Agents Effective in Specific Anemias1. Drugs Effective in Iron Deficiency & Other 1. Drugs Effective in Iron Deficiency & Other

Hypochromic AnemiasHypochromic Anemias 1.1 Iron & Iron Salts1.1 Iron & Iron Salts 1.2 Copper1.2 Copper 1.4 Pyridoxine 1.4 Pyridoxine 1.3 Cobalt1.3 Cobalt 1.5 Riboflavin 1.5 Riboflavin 2. Drugs for Megaloblastic Anemias2. Drugs for Megaloblastic Anemias 2.1 Vitamin B2.1 Vitamin B1212 2.2 Folic Acid 2.2 Folic Acid

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II. Drugs for Bleeding DisordersII. Drugs for Bleeding Disorders

A. CoagulantsA. Coagulants1. Vitamin K1. Vitamin K2. Local & Systemic Hemostatics2. Local & Systemic Hemostatics

B. AnticoagulantsB. Anticoagulants1. Heparin, Danaparoid, Lepirudin1. Heparin, Danaparoid, Lepirudin2. Oral Anticoagulants2. Oral Anticoagulants 2.1 Warfarin Sodium2.1 Warfarin Sodium 2.2 Dicumarol2.2 Dicumarol 2.3 Inandione derivatives 2.3 Inandione derivatives

(Anisindione)(Anisindione) 2.4 Phenprocoumon & Acenocoumarol2.4 Phenprocoumon & Acenocoumarol

C. Thrombolytic DrugsC. Thrombolytic Drugs1. Streptokinase1. Streptokinase2. Urokinase2. Urokinase3. Tissue Plasminogen Activator (t-PA)3. Tissue Plasminogen Activator (t-PA)

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D. Antiplatelet DrugsD. Antiplatelet Drugs

1. Aspirin1. Aspirin

2. Dipyridamole2. Dipyridamole

3. Ticlopidine3. Ticlopidine

4. Sulfinpyrazone4. Sulfinpyrazone

5. Clopidogrel (PLAVIX)5. Clopidogrel (PLAVIX)

6. Glycoprotein IIb/IIIa Inhibitors6. Glycoprotein IIb/IIIa Inhibitors

6.1 Abciximab (REOPRO) 6.1 Abciximab (REOPRO)

6.1 Eftifibatide (INTEGRILIN)6.1 Eftifibatide (INTEGRILIN)

6.2 Tirofiban (AGGRASTAT)6.2 Tirofiban (AGGRASTAT)

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THE HEMATOPOIETIC GROWTH FACTORSTHE HEMATOPOIETIC GROWTH FACTORS

History:History:1950s – role of cells from spleen & BM in restoration of 1950s – role of cells from spleen & BM in restoration of

hematopoietic tissues in irradiated ratshematopoietic tissues in irradiated rats – – defined the origin & action of erythropoietin defined the origin & action of erythropoietin

1961 – concept of colony-forming stem cells (CFUs) formed1961 – concept of colony-forming stem cells (CFUs) formed in spleen – are pluripotent in spleen – are pluripotent → progenitors (single→ progenitors (single CFUs) & to cells of increasing differentiationCFUs) & to cells of increasing differentiation

1906 – hematopoietine1906 – hematopoietine1977 – purification of erythropoietin1977 – purification of erythropoietin1985 – gene that encodes erythropoietin was cloned →1985 – gene that encodes erythropoietin was cloned →

recombinant hormonerecombinant hormone1985-1986 – complementary DNA & genomic clones for1985-1986 – complementary DNA & genomic clones for

granulocyte & macrophage stimulating factorsgranulocyte & macrophage stimulating factors1994 – sufficient quantities of WBC growth factors1994 – sufficient quantities of WBC growth factors

for clinical investigationfor clinical investigation

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General Characteristics:General Characteristics:

* Hematopoietic & lymphocytic GF – BM & * Hematopoietic & lymphocytic GF – BM & peripheral tissuesperipheral tissues

* Glycoproteins active at low concentrations* Glycoproteins active at low concentrations* Synergistic interactions; networking* Synergistic interactions; networking* Actions at several points* Actions at several points

ErythropoietinErythropoietin

Regulator of:Regulator of: 1. Proliferation of committed progenitors 1. Proliferation of committed progenitors

(BFU-E), CFU-E)(BFU-E), CFU-E) 2. Maturation of erythroblasts2. Maturation of erythroblasts 3. Release of reticulocytes3. Release of reticulocytes

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* Renal peritubular cells in cortex, few in liver* Renal peritubular cells in cortex, few in liver* 1* 1 gene product has 193 a.a residues gene product has 193 a.a residues* heavily glycosylated prolonging life in circ but not * heavily glycosylated prolonging life in circ but not ↑ ↑

biological activitybiological activity* Acts on early (BFU-E) & late (CFU-E) progenitor cells * Acts on early (BFU-E) & late (CFU-E) progenitor cells

to ↑ survival & terminal maturationto ↑ survival & terminal maturation* Surface receptors – changes in IC phosphorylation* Surface receptors – changes in IC phosphorylation * CRF, progressive RF, AIDS, Ca, selective surgery* CRF, progressive RF, AIDS, Ca, selective surgery* 15-50 U/kbw 3x a wk IV or SC (if IV half-life is 10 hrs * 15-50 U/kbw 3x a wk IV or SC (if IV half-life is 10 hrs

in CRF; if SC peak conc w/in 5-24 hrs); Hct det. a wk in CRF; if SC peak conc w/in 5-24 hrs); Hct det. a wk after – 4% ↑ in 2 wks → reduce doseafter – 4% ↑ in 2 wks → reduce dose

* * ↑ clotting of dialyzer; HPN & seizures↑ clotting of dialyzer; HPN & seizures

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Myeloid Growth FactorsMyeloid Growth Factors

* Glycoproteins in Recombinant forms:* Glycoproteins in Recombinant forms:1. GM-CSF 2. G-CSF 3. IL-3 4. M-CSF1. GM-CSF 2. G-CSF 3. IL-3 4. M-CSF5. thrombopoeitin5. thrombopoeitin

1. Stimulate proliferation & differentiation of 1or more myeloid cells lines1. Stimulate proliferation & differentiation of 1or more myeloid cells lines2. Enhances function of mature granulocytes & monocytes2. Enhances function of mature granulocytes & monocytes- produced by a no. of cells including fibroblasts, endothelial cells, produced by a no. of cells including fibroblasts, endothelial cells,

macrophages & T cellsmacrophages & T cells

A. Granulocyte/Macrophage Colony Stimulating FactorA. Granulocyte/Macrophage Colony Stimulating Factor ** Sargramostim Sargramostim – recombinant human GM-CSF– recombinant human GM-CSF

- 127 aa glycoprotein produced in yeast- 127 aa glycoprotein produced in yeast - substitution of a leucine in position 23 & variable levels of- substitution of a leucine in position 23 & variable levels of glycosylationglycosylation - 1- 1 effect is stimulation of myelopoiesis = effect is stimulation of myelopoiesis = ↑ BM cellularity & a ↑ BM cellularity & a shiftshift

in erythroid granulocyte ratio (E/G ratio) → neutrophils, in erythroid granulocyte ratio (E/G ratio) → neutrophils, eosinophils, monocytes; delays exit of neutrophils from eosinophils, monocytes; delays exit of neutrophils from circulationcirculation - especially useful in neutropenia (autologous BM transplantation,- especially useful in neutropenia (autologous BM transplantation, intensive chemotherapy. AIDS, aplastic anemia, myeloid intensive chemotherapy. AIDS, aplastic anemia, myeloid

dysplasia, 2 dysplasia, 2 to neoplasia) to neoplasia)

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- marketed as PROKINE, LEUKINE - marketed as PROKINE, LEUKINE - given SC, slow IV infusion at 125-500 ug/m- given SC, slow IV infusion at 125-500 ug/m22/day/day- plasma levels rise rapidly after SC then - plasma levels rise rapidly after SC then ↓ w/ half-↓ w/ half- life of 2-3 hrs; IV infusion maintained over 3-6 hrslife of 2-3 hrs; IV infusion maintained over 3-6 hrs- given daily; dose ↑ if no response after 7-14 days- given daily; dose ↑ if no response after 7-14 days- frequent blood counts- frequent blood counts- higher dose → pronounced side effects: bone- higher dose → pronounced side effects: bone pain, malaise, flu-like sy, diarrhea, dyspnea, rashpain, malaise, flu-like sy, diarrhea, dyspnea, rash

* extreme sensitivity → hypotension, dyspnea* extreme sensitivity → hypotension, dyspnea* prolonged adm → capillary leak syndrome →* prolonged adm → capillary leak syndrome →

peripheral edema, pleural & pericardial peripheral edema, pleural & pericardial effusioneffusion

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B. Granulocyte Colony-Stimulating Factor (G-CSF)B. Granulocyte Colony-Stimulating Factor (G-CSF)

* * FiligrastimFiligrastim – Reombinant Human G-CSF – Reombinant Human G-CSF - 175 aa glycoprotein produced in E. coli- 175 aa glycoprotein produced in E. coli - not glycosylated & carries an extra N-terminal methionine- not glycosylated & carries an extra N-terminal methionine

MOA:MOA:1. principal – stim. Of CFU-G to 1. principal – stim. Of CFU-G to ↑ neutrophil↑ neutrophil

2. enhances phagocytic & cytotoxic functions of neutrophils2. enhances phagocytic & cytotoxic functions of neutrophils - neutropenia in autologous BM transplantation, stem cell- neutropenia in autologous BM transplantation, stem cell

transplant, chemotherapy, bacterial & fungal infections, transplant, chemotherapy, bacterial & fungal infections, - marketed as Neupogen- marketed as Neupogen - SC or rapid IV infusion at 1-20 ug/kg/day- SC or rapid IV infusion at 1-20 ug/kg/day - distribution & clearance rate are similar to Sargramostim- distribution & clearance rate are similar to Sargramostim (half-life of 3-5 hrs)(half-life of 3-5 hrs) - AE: mild to moderate bone pain, local skin rxs, - AE: mild to moderate bone pain, local skin rxs, splenomegaly, granulocytosissplenomegaly, granulocytosis

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ThrombopoietinThrombopoietin

- under clinical trial- under clinical trial- Recombinant Human Thrombopoietin - Recombinant Human Thrombopoietin

(rHuTPO) & Pegylated Recombinant (rHuTPO) & Pegylated Recombinant Megakaryocyte Growth & Development Megakaryocyte Growth & Development Factor (PEG-rHyMGDF)Factor (PEG-rHyMGDF)

- a cytokine that actively stimulates - a cytokine that actively stimulates megakaryocytopoiesis megakaryocytopoiesis → increases → increases rapidly the platelet count in animals rapidly the platelet count in animals and is given in clinical trials of patients and is given in clinical trials of patients with high-dose chemotherapy (patients with high-dose chemotherapy (patients with gynecological ca given carboplatin)with gynecological ca given carboplatin)

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IRON AND IRON SALTSIRON AND IRON SALTS

- 4- 4thth most abundant element (O most abundant element (O22, silicon, Al), silicon, Al)

Importance: deficiency causesImportance: deficiency causes1. nutritional anemia (microcytic, hypochromic) - Hb, myoglobin 1. nutritional anemia (microcytic, hypochromic) - Hb, myoglobin & enzymes (heme, metalloflavoproteins for muscle metabolism)& enzymes (heme, metalloflavoproteins for muscle metabolism)2. behavioral & learning problems in children2. behavioral & learning problems in children3. abnormalities in catecholamine metabolism3. abnormalities in catecholamine metabolism4. heat production abnormality4. heat production abnormality

Hemoglobin = heme (Fe-protoporphyrin ring) + globinHemoglobin = heme (Fe-protoporphyrin ring) + globin

History:History: 1616thth – “chlorosis” or “green sickness” of adolescent female – “chlorosis” or “green sickness” of adolescent female

– – Sydenham identified Fe for specific Rx in place of bleedings & Sydenham identified Fe for specific Rx in place of bleedings & purgingspurgings

1717thth – Fe in blood – Fe in blood1919thth – “veritable pills of Blaud” (FeSo – “veritable pills of Blaud” (FeSo44 & K & K22COCO33))2020thth – transferrin, Fe metabolism – transferrin, Fe metabolism

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Iron metabolism:Iron metabolism:

Body Fe = Body Fe = 3-5 gms3-5 gms (essential & non-essential) (essential & non-essential)

Essential – HbEssential – Hb 65%65% myoglobinmyoglobin 4%4% heme & non-heme enzymesheme & non-heme enzymes } 1% } 1% transferrin-Fetransferrin-Fe } }

Storage Fe - ferritin (H2O soluble) (2/3)Storage Fe - ferritin (H2O soluble) (2/3) } } 30% 30%

- hemosiderin }- hemosiderin } (1/3) (1/3) (aggregated form)(aggregated form)

Flow of Fe = 30-40 mg/dayFlow of Fe = 30-40 mg/day

transferrin & ferritin are both fd in plasma & int’l mucosal cells transferrin & ferritin are both fd in plasma & int’l mucosal cells = = ↓ both ↓ both → ↑ → ↑ absorptionabsorption

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Iron Absorption:Iron Absorption:

* active transport in duodenum & proximal jejunum (NF-* active transport in duodenum & proximal jejunum (NF-E2, a regulatory transcription factor w/c links int’l E2, a regulatory transcription factor w/c links int’l transport to erythropoiesis under the overall control of transport to erythropoiesis under the overall control of a gene or chromosome 6)a gene or chromosome 6)

* in diet = heme & non-heme Fe* in diet = heme & non-heme Fe* 5-10 % absorption in diet w/ 10-15 elemental Fe* 5-10 % absorption in diet w/ 10-15 elemental Fe hemin (heme Fe & myoglobin) = 6% in diet but 30% hemin (heme Fe & myoglobin) = 6% in diet but 30%

absorbedabsorbed non-heme Fe & Fe in inorganic Fe salts & complexes = non-heme Fe & Fe in inorganic Fe salts & complexes =

Fe++ for absorption (Fe++ for absorption (↑ w/ HCl, vit C & meat; ↓ w/ ↑ w/ HCl, vit C & meat; ↓ w/ chelators or complexing agts, gastric resection, chelators or complexing agts, gastric resection, vegetarian diet)vegetarian diet)

* absorption in ↓ Fe stores & when erythropoiesis is * absorption in ↓ Fe stores & when erythropoiesis is increased & ineffective; increased & ineffective;

* Fe excretion: 1 mg/day = 2/3 in GIT, 1/3 thru skin & * Fe excretion: 1 mg/day = 2/3 in GIT, 1/3 thru skin & urineurine

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Iron DeficiencyIron Deficiency

Causes:Causes: 1. inadequate Fe intake in diet (growing children, pregnant, 1. inadequate Fe intake in diet (growing children, pregnant, lactating)lactating)2. 2. ↑ requirement of Fe due to blood loss (parasitism, GI or ↑ requirement of Fe due to blood loss (parasitism, GI or uterine)uterine)3. interference w/ Fe absorption (partial gastrectomy or sprue)3. interference w/ Fe absorption (partial gastrectomy or sprue)

Sequential ChangesSequential Changes::1. Negative Balance (Fe Depletion)1. Negative Balance (Fe Depletion) - reduction of Fe stores; plasma ferritin is <12 ug/L - reduction of Fe stores; plasma ferritin is <12 ug/L2. Fe-Deficient Erythropoiesis2. Fe-Deficient Erythropoiesis - suboptimal Fe supply to erythron; ↓ saturation of- suboptimal Fe supply to erythron; ↓ saturation of

transferrin to <15% &/or by ↑ above N in red cell porphyrintransferrin to <15% &/or by ↑ above N in red cell porphyrin3. Fe-Deficiency Anemia3. Fe-Deficiency Anemia - ↓ Hb; microcytic hypochromic RBC; ↓ plasma ferritin; ↑ red - ↓ Hb; microcytic hypochromic RBC; ↓ plasma ferritin; ↑ red cell cell

porphyrinporphyrin

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Treatment:Treatment:

Evaluate response after 1 wk byEvaluate response after 1 wk by1. reticulocyte production index1. reticulocyte production index2. concentration of Hb & Hct ( a measurable 2. concentration of Hb & Hct ( a measurable ↑ ↑

after 1 wk)after 1 wk)= an ↑ of 20 ug/L or > of Hb in 3-4 wks is considered= an ↑ of 20 ug/L or > of Hb in 3-4 wks is considered

a + response to Fe therapya + response to Fe therapy= if no response, stop treatment= if no response, stop treatment

1. Oral Fe = ferrous sulfate1. Oral Fe = ferrous sulfate1.1 Fe So4 USP (Feosol) – hydrated 20% elemental Fe; 1.1 Fe So4 USP (Feosol) – hydrated 20% elemental Fe;

dried is 30% dried is 30% 1.2 Ferrous fumarate, USP (FEOSTAT) = 33% Fe1.2 Ferrous fumarate, USP (FEOSTAT) = 33% Fe1.3 Ferrous gluconate, USP (FERGON) = 12 % Fe1.3 Ferrous gluconate, USP (FERGON) = 12 % Fe1.4 Ferrous lactate =19% Fe1.4 Ferrous lactate =19% Fe1.5 Polysaccharide-Fe complex (NIFEREX) = cpd of1.5 Polysaccharide-Fe complex (NIFEREX) = cpd of

ferrihydrite & CHOferrihydrite & CHO

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* duration of Rx is 3-6 months – correct anemia & replenish stores* duration of Rx is 3-6 months – correct anemia & replenish stores* ↑ of 20 g/L or more of Hb in 3-4 wks → + response* ↑ of 20 g/L or more of Hb in 3-4 wks → + response

* Untoward effects: 1* Untoward effects: 1° a function of amt of soluble Fe & psychological factors ° a function of amt of soluble Fe & psychological factors ( n, heartburn, upper GI discomfort, constipation, diarrhea)( n, heartburn, upper GI discomfort, constipation, diarrhea)* Chronic Fe toxicity: hemochromatosis, hemosiderosis (Fe in organs) * Chronic Fe toxicity: hemochromatosis, hemosiderosis (Fe in organs) → →

failure & deathfailure & deathRx: intermittent phlebotomyRx: intermittent phlebotomy

Fe chelation = deferoxamineFe chelation = deferoxamine

Acute Fe Poisoning:Acute Fe Poisoning:* 1-2 gms, but usly 2-10 gms in fatal cases* 1-2 gms, but usly 2-10 gms in fatal cases* S/S: GIT – abd’l pain, diarrhea or vomiting* S/S: GIT – abd’l pain, diarrhea or vomiting

cyanosis, lassitude, hyperventilation, CV collapse, comacyanosis, lassitude, hyperventilation, CV collapse, coma pyloric stenosis or gastric scarring, hemorrhagicpyloric stenosis or gastric scarring, hemorrhagic

gastroenteritis, hepatic damagegastroenteritis, hepatic damage* Death w/in 6 hrs or if not, 12-24 hrs after transient recovery* Death w/in 6 hrs or if not, 12-24 hrs after transient recovery* Plasma conc of Fe < 500 ug/dL or 3.5 mg/l = not in immediate danger* Plasma conc of Fe < 500 ug/dL or 3.5 mg/l = not in immediate danger* Rx is lavage w/ NaHCO* Rx is lavage w/ NaHCO3 3 or POor PO44 soln, vomiting, deferoxamine for > 500 soln, vomiting, deferoxamine for > 500

ug/dL; treat shock, acidosis, x-ray of stomachug/dL; treat shock, acidosis, x-ray of stomach* Speed of dx & Rx is impt = * Speed of dx & Rx is impt = ↓ mortality from 45% to 1%↓ mortality from 45% to 1%

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2. Parenteral Iron2. Parenteral Iron

* Fe stores rapidly created* Fe stores rapidly created* In dis. as sprue w/c prevents absorption; if oral Fe has * In dis. as sprue w/c prevents absorption; if oral Fe has

adverse effect on inflammatory. disease of the bowel; & adverse effect on inflammatory. disease of the bowel; & in intolerance to oral Fein intolerance to oral Fe

Preparations:Preparations:2.1 Fe dextran injection, USP (IMFERON) (INFED)2.1 Fe dextran injection, USP (IMFERON) (INFED)

Ferric oxyhydroxide w/ dextran in colloidal solnFerric oxyhydroxide w/ dextran in colloidal soln contg 50 mg/ml Fe given IM or IV (test)contg 50 mg/ml Fe given IM or IV (test)

2.2 Iron-polycomplex (SORBITOL GLUCONIC ACID) 2.2 Iron-polycomplex (SORBITOL GLUCONIC ACID) – – only given IMonly given IM

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B12 & FOLIC ACIDB12 & FOLIC ACID

Deficiency: defective synthesis of DNA Deficiency: defective synthesis of DNA → megaloblastic anemia→ megaloblastic anemia

Relationship between B12 & Folic acid:Relationship between B12 & Folic acid:> Intracellular B12 is maintained as 2 active coenzymes> Intracellular B12 is maintained as 2 active coenzymes1. deoxyadenosylcobalamin1. deoxyadenosylcobalamin

= a cofactor for the mitochondrial mutase enzyme that= a cofactor for the mitochondrial mutase enzyme that catalyzes the isomerization of L-methyl malonyl CoA tocatalyzes the isomerization of L-methyl malonyl CoA to

succinyl CoA an impt rx in both CHO & lipid metabolismsuccinyl CoA an impt rx in both CHO & lipid metabolism2. methylcobalamin (CH2. methylcobalamin (CH33B12)B12)

= supports the methionine synthetase rx w/c is essential for= supports the methionine synthetase rx w/c is essential for normal metabolism of folate (folate cofactors recycling, normal metabolism of folate (folate cofactors recycling, folylpolyglutamates IC conc, methylation rxs thru thefolylpolyglutamates IC conc, methylation rxs thru the synthesis of methionine & its product s-adenosylmethionine synthesis of methionine & its product s-adenosylmethionine

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= methyl gps contributed by methyltetrahydroflolate (CH= methyl gps contributed by methyltetrahydroflolate (CH33HH44PteGluPteGlu11) are used ) are used to form methylcobalamin w/c then acts as methyl gp donor for the to form methylcobalamin w/c then acts as methyl gp donor for the conversion of homocysteine to methionine conversion of homocysteine to methionine → this folate-cobalamin → this folate-cobalamin interaction is pivotal for normal synthesis of purines & pyrimidines (DNA)interaction is pivotal for normal synthesis of purines & pyrimidines (DNA)

= methyl TH= methyl TH44 is the principal folate congener & 1° source of methyl gps for is the principal folate congener & 1° source of methyl gps for formation of methionineformation of methionine

= tetrahydrofolate (H= tetrahydrofolate (H44PteGluPteGlu11) is a substrate for many metbolic steps:) is a substrate for many metbolic steps:1. precursor of IC folypolyglutamates1. precursor of IC folypolyglutamates2. acceptor of a 1-carbon unit in conversion of serine to glycine 2. acceptor of a 1-carbon unit in conversion of serine to glycine

& formation og 5,10-methylene THF (5,10-CH& formation og 5,10-methylene THF (5,10-CH22-H-H44PteGluPteGlu11) →) → donate methylene gp to deoxyuridylate to form thymidylate,donate methylene gp to deoxyuridylate to form thymidylate,

an impt rx in DNA synthesis, & dihydrofolate w/c is reduced an impt rx in DNA synthesis, & dihydrofolate w/c is reduced by dihydrofolate reductase to THFby dihydrofolate reductase to THF

Def of B12 & Folic acidDef of B12 & Folic acid → ↓ synthesis of methionine & s-adenosylmethionine → ↓ synthesis of methionine & s-adenosylmethionine →→1. interferes w/ protein biosynthesis, methylation rxs & snythesis of 1. interferes w/ protein biosynthesis, methylation rxs & snythesis of polyaminespolyamines2. cells redirect folate metabolism pathways → ↑ methylTHF w/c tends to 2. cells redirect folate metabolism pathways → ↑ methylTHF w/c tends to preserve essential methylation rxs at the expense of nucleic acid preserve essential methylation rxs at the expense of nucleic acid synthesissynthesis

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B12 (CYANOCOBALAMIN)B12 (CYANOCOBALAMIN)

Chemistry:Chemistry: 3 major protions 3 major protions1. corrin nucleus = porphyrin ring, w/ 4 reduced pyrrole rings linked to a1. corrin nucleus = porphyrin ring, w/ 4 reduced pyrrole rings linked to a central cobalt atom & extensively substituted w/ methyl, acetamide &central cobalt atom & extensively substituted w/ methyl, acetamide & propionamide residuespropionamide residues2. 5,6-dimethylbenzimidazolyl nucleotide2. 5,6-dimethylbenzimidazolyl nucleotide3. a variable R gp – impt ones are fd in cyanocobalamin, 3. a variable R gp – impt ones are fd in cyanocobalamin, hydroxocobalaminhydroxocobalamin & coenzymes methycobalamin & 5-deoxyyadenosylcobalamin& coenzymes methycobalamin & 5-deoxyyadenosylcobalamin

= from Streptomyces culture= from Streptomyces culture

Pharmacodynamics:Pharmacodynamics:2 essentail enzymatic rxs:2 essentail enzymatic rxs:1. 1.1 deoxyadenosylcobalamin is a cofactor in conversion of methylmalonyl 1. 1.1 deoxyadenosylcobalamin is a cofactor in conversion of methylmalonyl

CoA by methylmalonyl CoA mutaseCoA by methylmalonyl CoA mutase= in B12 def = in B12 def → methylmalonyl CoA accumulates → aberrant fatty acids → methylmalonyl CoA accumulates → aberrant fatty acids into into cell membrane of CNS → neurological manifestationcell membrane of CNS → neurological manifestation

1.2. methylcobalamin supports the methionine synthetase rx1.2. methylcobalamin supports the methionine synthetase rx= def of methionine synthetase blocks conversion of methionine to = def of methionine synthetase blocks conversion of methionine to s-adensylmethionine involved in methylation rxs for synthesis of s-adensylmethionine involved in methylation rxs for synthesis of phospholipids & myelin → myelin damage phospholipids & myelin → myelin damage

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2. conversion of 5-methyTHF & homocysteine to THF &2. conversion of 5-methyTHF & homocysteine to THF &

methionine by 5-CHmethionine by 5-CH33THF homocysteine THF homocysteine methyltransferasemethyltransferase= in B12 def: conversion to THF cannot occur (methyTHF = in B12 def: conversion to THF cannot occur (methyTHF trap) trap)

→ → def of folate cofactors for DNA synthesis → def of folate cofactors for DNA synthesis → megalobalsticmegalobalstic anemiaanemia

Sources in Nature:Sources in Nature:* Microorganisms in soil, sewage, water, or int’l lumen* Microorganisms in soil, sewage, water, or int’l lumen* bact’l synthesis (meat esp liver, eggs, dairy products)* bact’l synthesis (meat esp liver, eggs, dairy products)* Plants contaminated w/ bacteria* Plants contaminated w/ bacteria* Small amt in contaminated legumes* Small amt in contaminated legumes

Human minimum requirement: 1 ug/day so daily Human minimum requirement: 1 ug/day so daily nutritional req of 3-5 ug from animal by-productsnutritional req of 3-5 ug from animal by-products

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Pharmacokinetics:Pharmacokinetics:* Quantitatively & rapidly absorbed fr IM & SC → peak plasma w/in 1 * Quantitatively & rapidly absorbed fr IM & SC → peak plasma w/in 1

hr after IMhr after IM* Absorption from GIT: dietary B12 in presence of gastric acid & * Absorption from GIT: dietary B12 in presence of gastric acid &

pancreatic proteases is released from proteins + intrinsic factor pancreatic proteases is released from proteins + intrinsic factor from gastric parietal cells → to ileum for absorption (needs also bile from gastric parietal cells → to ileum for absorption (needs also bile & suitable pH >6) → in plasma bd to transcobalamin II → tissues & suitable pH >6) → in plasma bd to transcobalamin II → tissues esp hepatic parenchymal cells fr 1-10 mg → excretion in bile esp hepatic parenchymal cells fr 1-10 mg → excretion in bile (enterohepatic circ) & a little in kidneys(enterohepatic circ) & a little in kidneys

* 3-4 yrs before S/S of def develop* 3-4 yrs before S/S of def develop* Normal plasma B12 is 200-900 pg/ml; def state is < 200 pg/ml* Normal plasma B12 is 200-900 pg/ml; def state is < 200 pg/mlDecreased absorptionDecreased absorption in: in:1. Gastric achlorydia + ↓ if secretion 2° to gastric atrophy or gastric 1. Gastric achlorydia + ↓ if secretion 2° to gastric atrophy or gastric

surgery ( pernicious anemia)surgery ( pernicious anemia)2. Pancreatic disorder = ↓ pancreatic proteases2. Pancreatic disorder = ↓ pancreatic proteases3. Antibodies to IF or to IF-B12 complex3. Antibodies to IF or to IF-B12 complex4. bact’l overgrowth or int’l parasites4. bact’l overgrowth or int’l parasites5. Damage to ileal mucosal cells5. Damage to ileal mucosal cells

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Other Causes of B12 deficiency:Other Causes of B12 deficiency:

1. Strict vegetarians1. Strict vegetarians2. Congenital absence of transcobalamin2. Congenital absence of transcobalamin3. Rapid depletion of heaptic stores by interfernece in enterohepatic circ3. Rapid depletion of heaptic stores by interfernece in enterohepatic circ4. Appearance of abnormal amts of transcobalamin I & III in plasma4. Appearance of abnormal amts of transcobalamin I & III in plasma5. Defects in IC metabolism of vit B12 in children w/ methylmalonic aciduria 5. Defects in IC metabolism of vit B12 in children w/ methylmalonic aciduria

& homocystinuria& homocystinuria

B12 deficiency B12 deficiency → ineffective hematopoiesis→ ineffective hematopoiesis1. Megalobalstic a. (Addison or pernicious a.)1. Megalobalstic a. (Addison or pernicious a.)2. Irreversible damage to the nervous system2. Irreversible damage to the nervous system3. Abnormalities of epith tissue particularly of the GIT3. Abnormalities of epith tissue particularly of the GIT

Diagnosis:Diagnosis:1. Plasma concentration determination1. Plasma concentration determination2. Gastric function tests2. Gastric function tests3. Reticulocytosis3. Reticulocytosis4. Urinary methylmalonate (N exc is 0-3.5 mg/day; def is 300 mg/day) & 4. Urinary methylmalonate (N exc is 0-3.5 mg/day; def is 300 mg/day) &

serum methylmalonateserum methylmalonate

Schilling test = serum or urine methylmalonate determination & Schilling test = serum or urine methylmalonate determination & reticulocytosis following therapeutic trial of B12reticulocytosis following therapeutic trial of B12

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General Principles of Therapy:General Principles of Therapy:1. B12 given prophylactically only in reasonable 1. B12 given prophylactically only in reasonable

indications as strict vegetarians, following gastrectomy, indications as strict vegetarians, following gastrectomy, certain dis of the SIcertain dis of the SI

2. Full investigation of etiology2. Full investigation of etiology3. Specific therapy3. Specific therapy4. Acutely ill & elderly patients = blood transfusion & 4. Acutely ill & elderly patients = blood transfusion &

immediate treatment w/ folic acid & B12immediate treatment w/ folic acid & B125. Long term therapy – evaluate every 6-12 mos.5. Long term therapy – evaluate every 6-12 mos.6. give 100-1000 mg/day or q other day for 1-2 wks to 6. give 100-1000 mg/day or q other day for 1-2 wks to

replenish stores replenish stores → Maintenance every month→ Maintenance every month

Preparations:Preparations:1. Cyanocobalamin inj, USP (RUBRAMIN, REDISOL) IM or 1. Cyanocobalamin inj, USP (RUBRAMIN, REDISOL) IM or

deep SC 1 ug for 10 daysdeep SC 1 ug for 10 days2. Hydroxocobalamin (CODROXOMIN, ALPHAREDISOL) = 2. Hydroxocobalamin (CODROXOMIN, ALPHAREDISOL) =

more highly protein boundmore highly protein bound

2828

FOLIC ACID (PteGlu1)FOLIC ACID (PteGlu1)((Pteroylglutamic Acid, Vit M, Brewer’s Yeast)Pteroylglutamic Acid, Vit M, Brewer’s Yeast)

= bact’l growth factor in spinach leaves= bact’l growth factor in spinach leaves= purified in 1943; synthesized in 1945= purified in 1943; synthesized in 1945

Chemistry & Metabolic Functions:Chemistry & Metabolic Functions:= pteridine ring linked by a methylene bridge to PABA, = pteridine ring linked by a methylene bridge to PABA,

w/c is joined by an amide linkage to glutamic acidw/c is joined by an amide linkage to glutamic acid= after absorption FA is rapidly reduced to THF w/c acts = after absorption FA is rapidly reduced to THF w/c acts

as an acceptor of a no. of 1-carbon units:as an acceptor of a no. of 1-carbon units:1. conversion of homocysteine to methionine1. conversion of homocysteine to methionine2. conversion of serine to glycine2. conversion of serine to glycine3. synthesis of thymidylate3. synthesis of thymidylate4. histidine metabolism4. histidine metabolism5. synthesis of purines5. synthesis of purines6. utilization or generation of formates6. utilization or generation of formates

2929

Sources & Daily Requirements:Sources & Daily Requirements:= nearly all foods – yeast, liver, fresh green vegetables, = nearly all foods – yeast, liver, fresh green vegetables,

some fruitssome fruits= 50-90% destroyed by cooking & canning= 50-90% destroyed by cooking & canning= as conjugates (reduced polyglutamates)= as conjugates (reduced polyglutamates)= req is 50 ug/day; pregnant & lactating 100-200 ug= req is 50 ug/day; pregnant & lactating 100-200 ug

Pharmacokinetics:Pharmacokinetics:= diet – 500-700 ug; absorbed is 50-200 ug= diet – 500-700 ug; absorbed is 50-200 ug= absorption in prox SI; needs action & transport of a = absorption in prox SI; needs action & transport of a

pteroyl-pteroyl--glutamyl carboxypeptidase ass w/ mucosal -glutamyl carboxypeptidase ass w/ mucosal membrane membrane → methylated to methylTHF by dihydrofolate → methylated to methylTHF by dihydrofolate reductase fd in duodenal & upper jejunal mucosa → reductase fd in duodenal & upper jejunal mucosa → tissues where methylTHF donates methyl to form tissues where methylTHF donates methyl to form methylcobalamin & as a source of other folate congenersmethylcobalamin & as a source of other folate congeners

= if stored, as polyglutamates esp in liver cells if stored, = if stored, as polyglutamates esp in liver cells if stored, as polyglutamates esp in liver cells → enterohepatic as polyglutamates esp in liver cells → enterohepatic circulationcirculation

= small amts excreted in urine= small amts excreted in urine

3030

Folate Deficiency:Folate Deficiency:

= develops in 1-6 months= develops in 1-6 months= in diseases of SI; other causes are= in diseases of SI; other causes are

1. chronic alcoholism1. chronic alcoholism2. dis w/ high level of turnover (cong hemolytic a)2. dis w/ high level of turnover (cong hemolytic a)3. drugs: inhibit dihydrofolate reductase = methotrexate, 3. drugs: inhibit dihydrofolate reductase = methotrexate, trimethoprimtrimethoprim

interferes w/ absorption & storage = INH, certain interferes w/ absorption & storage = INH, certain anticonvulsants, anticonvulsants,

oral anticoagulantsoral anticoagulants= megaloblastic a. rarely w/ neurologic s/s= megaloblastic a. rarely w/ neurologic s/s= more rapid in onset then B12 def (1-4 wks)= more rapid in onset then B12 def (1-4 wks)= Dx: plasma & cell folate conc = N is 4-20 ng/ml= Dx: plasma & cell folate conc = N is 4-20 ng/ml

Adverse Effects:Adverse Effects:

= rare; oral folic acid non-toxic even in high dose= rare; oral folic acid non-toxic even in high dose= rare allergic rx to parenteral= rare allergic rx to parenteral= counteract antiepeleptic effect of phenobarbital, phenytoin, = counteract antiepeleptic effect of phenobarbital, phenytoin,

primidone primidone ((↑ frequency of seizures in children)↑ frequency of seizures in children)

3131

General Principles of Therapy:General Principles of Therapy:1. prophylaxis in clear indications1. prophylaxis in clear indications

1.1 pregnancy or lactation since 50 ug/day lost in milk; multvit of 400-500 1.1 pregnancy or lactation since 50 ug/day lost in milk; multvit of 400-500 ugug1.2 disease of high cell turnover1.2 disease of high cell turnover1.3 drug-induced1.3 drug-induced

2. careful evaluation to determine etiology2. careful evaluation to determine etiology3. specific therapy3. specific therapy4. potential cx of mistreatment of B12 def w/ FA must be kept in mind4. potential cx of mistreatment of B12 def w/ FA must be kept in mind

Preparations:Preparations:1. Folic acid , USP tab (FOLVITE)1. Folic acid , USP tab (FOLVITE)2. Folic acid Inj = aqeous soln of Na salt of folic acid2. Folic acid Inj = aqeous soln of Na salt of folic acid3. Leucovorin Ca Inj, USP (folinic acid, citrovorum factor)3. Leucovorin Ca Inj, USP (folinic acid, citrovorum factor)

= marketed as WELLCOVORIN= marketed as WELLCOVORIN= also comes in tablets= also comes in tablets= formyl derivative of THF & this can be used when the body fails to effect = formyl derivative of THF & this can be used when the body fails to effect the conversion of FAthe conversion of FA= principal indication is to circumvent the action of inhibition of = principal indication is to circumvent the action of inhibition of dihydrofolate dihydrofolate reductase reductase

3232

HemostasisHemostasis

= control & prevention of blood loss= control & prevention of blood loss

Vascular phase → platelet phase → Vascular phase → platelet phase → coagulation phase (activation of the coagulation phase (activation of the intrinsic & extrinsic pathways) intrinsic & extrinsic pathways)

3 steps in coagulation:3 steps in coagulation: 1. formation of prothrombin activators 1. formation of prothrombin activators which 2. convert prothrombin to which 2. convert prothrombin to thrombin which thrombin which 3. converts fibrinogen to fibrin3. converts fibrinogen to fibrin

3333

COAGULANT, ANTICOAGULANT, THROMBOLYTIC & COAGULANT, ANTICOAGULANT, THROMBOLYTIC & ANTIPLATELET DRUGSANTIPLATELET DRUGS

Hemostasis:Hemostasis:1. Vasospasm1. Vasospasm2. Formation of platelet plug2. Formation of platelet plug3. Blood coagulation3. Blood coagulation4. Growth of fibrous tissue (fibroblasts)4. Growth of fibrous tissue (fibroblasts)

Blood coagulation = zymogen factors (protease zymogens as VII, IX, Blood coagulation = zymogen factors (protease zymogens as VII, IX, X, XI, XII, non-enzymatic factors V, VIII)X, XI, XII, non-enzymatic factors V, VIII)

1. Formation of prothrombin activator (X1. Formation of prothrombin activator (Xaa) w/ help of V) w/ help of Vaa, , phospholipids, Caphospholipids, Ca++++

1.1 intrinsic system1.1 intrinsic system1.2 extrinsic system1.2 extrinsic system

2. Conversion of prothrombin to thrombin2. Conversion of prothrombin to thrombin3. Conversion of fibrinogen to fibrin3. Conversion of fibrinogen to fibrin

Thromboxane AThromboxane A22

Prostacyclin (PGIProstacyclin (PGI22) = inhibits thrombosis) = inhibits thrombosisPlasminogen (profibrinolysin)Plasminogen (profibrinolysin)

3434

3535

3636

Thrombogenesis Thrombogenesis = altered state of hemostasis; stasis, = altered state of hemostasis; stasis, hypercoagulability, & change of the vessel wallhypercoagulability, & change of the vessel wall

Thrombus:Thrombus:1. white or arterial thrombus (platelets) 1. white or arterial thrombus (platelets) → ischemia→ ischemia2. red or venous thrombus (fibrin network w/ RBC & platelets)2. red or venous thrombus (fibrin network w/ RBC & platelets)

= areas of stasis → embolization; edematous & inflamed tissue= areas of stasis → embolization; edematous & inflamed tissue3. mixed white & red thrombus3. mixed white & red thrombus

Coagulation in vitro:Coagulation in vitro:= blood clots in 4-8 mins= blood clots in 4-8 mins= prevented by EDTA (ethylene-diaminetetraacetic acid) or citrate = prevented by EDTA (ethylene-diaminetetraacetic acid) or citrate

w/c binds Caw/c binds Ca++++

= recalcified plasma clots in 2-4 mins= recalcified plasma clots in 2-4 mins

1. activated partial thromboplastin time (aPTT) = 26-33 secs1. activated partial thromboplastin time (aPTT) = 26-33 secs* + neg. charged phospholipids & kaolin (Al silicate)* + neg. charged phospholipids & kaolin (Al silicate)

2. Prothrombin time (PT) = 12-14 secs2. Prothrombin time (PT) = 12-14 secs* add “ thromboplastin”, a saline extract of brain that contains * add “ thromboplastin”, a saline extract of brain that contains tissue factor &tissue factor &

phosphlipidsphosphlipids

3737

Prolonged aPTT & a normal PT = defective intrinsic coagulationProlonged aPTT & a normal PT = defective intrinsic coagulationProlonged PT & normal aPTT = defect in extrinsic coagulationProlonged PT & normal aPTT = defect in extrinsic coagulationProlonged PT & aPTT = defect in common pathProlonged PT & aPTT = defect in common path

Natural Anticoagulant Mechanisms:Natural Anticoagulant Mechanisms:1. Intact blood vessel1. Intact blood vessel2. Prostacyclin (PGI2. Prostacyclin (PGI22))3. Anttithrombin3. Anttithrombin4. Heparin sulfate proteoglycans4. Heparin sulfate proteoglycans5. Protein C- plasma zymogen that degrades factors V5. Protein C- plasma zymogen that degrades factors Va a and VIIIand VIIIaa

6. Fibrinolysin6. Fibrinolysin7. Tissue factor pathway inhibitor (TFPI) = inhibits factors X7. Tissue factor pathway inhibitor (TFPI) = inhibits factors Xa a & VII& VIIaa

COAGULANTSCOAGULANTS

Vitamin K (fat soluble)Vitamin K (fat soluble)= 2 naturally occurring vit K (lipid soluble)= 2 naturally occurring vit K (lipid soluble)

1. K1 (phylloquinone or phytonadione) = plants1. K1 (phylloquinone or phytonadione) = plants2. K2 (menaquinones) = alimentary tract2. K2 (menaquinones) = alimentary tract

= K3 (menadione) = synthetic; quinone; can be water soluble= K3 (menadione) = synthetic; quinone; can be water soluble= bile needed= bile needed= requirement is 0.5-1.0 ug/kg/day = requirement is 0.5-1.0 ug/kg/day

3838

Vit K DeficiencyVit K Deficiency

1. Abnormal alimentary tract flora = newborns, antimicrobials1. Abnormal alimentary tract flora = newborns, antimicrobials2. Bile failing to enter intestine = obstructive jaundice, biliary fistula2. Bile failing to enter intestine = obstructive jaundice, biliary fistula3. Certrain malabsorption syndromes = sprue, extensive SI 3. Certrain malabsorption syndromes = sprue, extensive SI

resectomyresectomy4. Excessive intake of vit A 4. Excessive intake of vit A

= inhibits bacterial synthesis= inhibits bacterial synthesis = antagonizes hepatic action of vit K= antagonizes hepatic action of vit K

= increased tendency to bleed= increased tendency to bleed

HEPARIN & ORAL ANTICOAGULANTSHEPARIN & ORAL ANTICOAGULANTS

Two types of anticoagulantsTwo types of anticoagulants1. Direct acting = heparin1. Direct acting = heparin

= rapidly effective; few hours action; parenteral= rapidly effective; few hours action; parenteral= in vitro & in vivo= in vitro & in vivo= antagonized by protamine sulfate= antagonized by protamine sulfate

2. Indirect acting = coumarin, warfarin2. Indirect acting = coumarin, warfarin= 16-72 hrs effect; several days; oral or parenteral= 16-72 hrs effect; several days; oral or parenteral= vit K is antagonist; in vivo= vit K is antagonist; in vivo

3939

HEPARINHEPARIN

History:History:1916 = J. McLean: cell-promoting activity of phosphatides 1916 = J. McLean: cell-promoting activity of phosphatides → liver-→ liver-

phospholipid phospholipid anticoagulantanticoagulant

1922 = Howell: heparin (water soluble mucopolyssacharide)1922 = Howell: heparin (water soluble mucopolyssacharide)

Chemistry & Source:Chemistry & Source:= glycosaminoglycan= glycosaminoglycan= a complex linear polysaccharide of 60,000-100,000 daltons covalently = a complex linear polysaccharide of 60,000-100,000 daltons covalently

attached to a core protein that is found in mast cell secretory granules; attached to a core protein that is found in mast cell secretory granules; also fd in surface of most eukaryocytic cells & in the EC matrix (Heparin also fd in surface of most eukaryocytic cells & in the EC matrix (Heparin SOSO44))

1. Heparin & Heparin sulfate1. Heparin & Heparin sulfate= synthesized as a polymer of alternating D-glucuronic acid & N-acetyl-D-= synthesized as a polymer of alternating D-glucuronic acid & N-acetyl-D- glucosamine residuesglucosamine residues= strongly acidic – covalently linked sulfate & carboxylic acid gps= strongly acidic – covalently linked sulfate & carboxylic acid gps= commercial heparin = bovine lung, porcine int’l mucosa; sheep & whale= commercial heparin = bovine lung, porcine int’l mucosa; sheep & whale

2. Dermatan sulfate2. Dermatan sulfate= repeating polymer of L-iduronic acid & N-acetyl-D-glucosamine= repeating polymer of L-iduronic acid & N-acetyl-D-glucosamine= from same sources as heparin= from same sources as heparin

4040

Pharmacological Properties:Pharmacological Properties:= given IV; has 2 major effects= given IV; has 2 major effects1. Impairment of blood coagulation1. Impairment of blood coagulation2. Reduction of plasma triglycerides2. Reduction of plasma triglycerides

Mechanism of Action:Mechanism of Action:

1. Impairment of blood coagulation1. Impairment of blood coagulation= acts w/ antithrombin III, an = acts w/ antithrombin III, an αα-globulin that rapidly inhibits thrombin only -globulin that rapidly inhibits thrombin only in the presence of heparinin the presence of heparin= acts as a catalytic template to w/c antithrombin & a serine protease = acts as a catalytic template to w/c antithrombin & a serine protease bind →bind →

rate of thrombin-antithrombin rx rate of thrombin-antithrombin rx by at elast 1000x & also inhibits by at elast 1000x & also inhibits activated coagulation factors of the intrinsic & common pathways (Xactivated coagulation factors of the intrinsic & common pathways (Xaa, ,

IXIXaa,, XIXIaa, XII, XIIaa & kallikrein) → tertiary complex formed & kallikrein) → tertiary complex formed

= interferes w/ platelet aggregation= interferes w/ platelet aggregation2. Reduces the lipemia following a fatty meal2. Reduces the lipemia following a fatty meal

= releasing into circ tissue-bound lipid-hydrolyzing enzymes, as = releasing into circ tissue-bound lipid-hydrolyzing enzymes, as lipoproteinlipoprotein

lipase, w/c hydrolyzes the triglycerides of chylomicrons & VLDL to cap lipase, w/c hydrolyzes the triglycerides of chylomicrons & VLDL to cap endothelial cells into FA & partial glycerides or glycerol endothelial cells into FA & partial glycerides or glycerol

4141

Antithrombin (Antithrombin III)Antithrombin (Antithrombin III)

= glycosylated single chain polypeptide w/ a mass of about 58 KDa; = glycosylated single chain polypeptide w/ a mass of about 58 KDa; synthesized in liversynthesized in liver

1. Inhibits thrombin only in the presence of heparin1. Inhibits thrombin only in the presence of heparin= homologous to = homologous to αα1-antitrypsin family of protease inhibitors, 1-antitrypsin family of protease inhibitors, serpins (serine protease inhibitors)serpins (serine protease inhibitors)

2. Inhibits activated coag factors of intrinsic & common pathways2. Inhibits activated coag factors of intrinsic & common pathways= is a “suicide substrate” for the proteases w/c attack a specific arg-= is a “suicide substrate” for the proteases w/c attack a specific arg-

ser peptide bond in reactive sites of antithrombin → trapped as a ser peptide bond in reactive sites of antithrombin → trapped as a stable 1:1 complexstable 1:1 complex

Pharmacokinetics:Pharmacokinetics:= crosses membrane poorly (polarity & large molecular size)= crosses membrane poorly (polarity & large molecular size)= low doses given SC or intrafat; high doses given IV, continuous or = low doses given SC or intrafat; high doses given IV, continuous or

intermittent ; IM = hematomaintermittent ; IM = hematoma= in blood, evenly distributed bet WBC & plasma (half-life = in blood, evenly distributed bet WBC & plasma (half-life

dependent on dose) → liver by heparinase into inactive products dependent on dose) → liver by heparinase into inactive products (uroheparin) → urine(uroheparin) → urine

4242

Adverse Effects, Toxicity, Contraindications:Adverse Effects, Toxicity, Contraindications:

* Purified commercial prep = non-toxic, low AE* Purified commercial prep = non-toxic, low AEMajor:Major:1. Hemorrhage (1-33%)1. Hemorrhage (1-33%)2. Thrombocytopenia (reversible)2. Thrombocytopenia (reversible)

2.1 transient & mild (not <100,000/uL) = 2-5%2.1 transient & mild (not <100,000/uL) = 2-5% 2.2 severe = heparin-dependent antiplatelet antibodies2.2 severe = heparin-dependent antiplatelet antibodies

Minor:Minor:Hypersensitivity, alopecia, osteoporosis & spontaneous fractures, Hypersensitivity, alopecia, osteoporosis & spontaneous fractures,

hepatic function abnormalities, hyperkalemia, inhibit aldosterone hepatic function abnormalities, hyperkalemia, inhibit aldosterone synthesissynthesis

Contraindications:Contraindications:1. Pats who consume large amts of ethanol; sensitive to the drug; 1. Pats who consume large amts of ethanol; sensitive to the drug;

active bleeding or bleeding tendenciesactive bleeding or bleeding tendencies2. During & after surgery of brain, eye, spinal cord2. During & after surgery of brain, eye, spinal cord3. Lumbar puncture or regional anesthesia3. Lumbar puncture or regional anesthesia

4343

Antagonist= protamine sulfateAntagonist= protamine sulfate

= protamines are proteins in spoerm or mature testes of fish of the = protamines are proteins in spoerm or mature testes of fish of the family salmonidaefamily salmonidae

= strongly basic (arginine)= strongly basic (arginine)= in vitro, bind tightly to heparin = in vitro, bind tightly to heparin → neutralize→ neutralize= in vivo, inhibits anticoag effect of heparin; w/o heparin, interacts = in vivo, inhibits anticoag effect of heparin; w/o heparin, interacts

w/ platelets, fibrinogen & other plasma CHONs → anticoagulant w/ platelets, fibrinogen & other plasma CHONs → anticoagulant effecteffect

= protamine sulfate Inj, USP 10 mg/ml IV slowly= protamine sulfate Inj, USP 10 mg/ml IV slowly

Preparations:Preparations:1. Heparin Na Inj = lipo-hepin/Bl (bovine lung); Lipo-hepin, 1. Heparin Na Inj = lipo-hepin/Bl (bovine lung); Lipo-hepin,

Liquaemin Na (porcine intestine)Liquaemin Na (porcine intestine)2. Heparin Ca Inj (CALCIPARINE)2. Heparin Ca Inj (CALCIPARINE)3. Low molecular weight heparin3. Low molecular weight heparin= deep SC or intrafat= deep SC or intrafat= intermittent IV therapy (heparin lock)= intermittent IV therapy (heparin lock)= continuous IV infusion (pump)= continuous IV infusion (pump)= intrapulmonary administration (aerolized)= intrapulmonary administration (aerolized)

4444

ORAL ANTICOAGULANTSORAL ANTICOAGULANTSHistory:History:1924 Schofeld = “sweet clover dis” (cattle) – spoiled 1924 Schofeld = “sweet clover dis” (cattle) – spoiled

sweet clover silagesweet clover silage Campbell & Link = identified bishydroxycoumarin Campbell & Link = identified bishydroxycoumarin

(dicumarol)(dicumarol)1944 Ikawa = racemic warfarin (Wisconsin Alumni 1944 Ikawa = racemic warfarin (Wisconsin Alumni

Research Foundation)Research Foundation)warfarin was a rodenticidewarfarin was a rodenticide

Chemistry:Chemistry:Bishydroxycoumarin = derivative of 4-hydroxycoumarin & Bishydroxycoumarin = derivative of 4-hydroxycoumarin &

indan1-3-dione, a related cpd; there is an intact 4-indan1-3-dione, a related cpd; there is an intact 4-hydroxycoumarin residue w/ a carbon substituent at the hydroxycoumarin residue w/ a carbon substituent at the 3 position3 position

Pharmacologic Properties:Pharmacologic Properties:Racemic warfarin Na = prototype; drug of choiceRacemic warfarin Na = prototype; drug of choice

4545

MOA:MOA:

= antagonists of vit K= antagonists of vit K

= coag factors II, VII, IX, X & the anticoagulant CHONs = coag factors II, VII, IX, X & the anticoagulant CHONs C & S are biologically inactive unless certain C & S are biologically inactive unless certain glutamic acid residues (9-12 in no) are carboxylated glutamic acid residues (9-12 in no) are carboxylated by a microsomal enzyme system that utilizes by a microsomal enzyme system that utilizes reduced vit K as a cofactor reduced vit K as a cofactor → modified → modified --carboxyglutamate (Gla) residues confer Cacarboxyglutamate (Gla) residues confer Ca++ ++ binding binding

propertiesproperties essential essential for becoming an efficeent for becoming an efficeent catalytic complex catalytic complex

= in the metabolism of vit K, the conversion of vit K = in the metabolism of vit K, the conversion of vit K epoxide back to vit KHepoxide back to vit KH2,, 2,, (hydroquinone), a reduction, (hydroquinone), a reduction,

,,is probably the site of action of warfarin & the site of is probably the site of action of warfarin & the site of genetic resistance to warfarin (block)genetic resistance to warfarin (block)

4646

Pharmacokinetics:Pharmacokinetics:= dicumarol is irregularly absorbed from GIT= dicumarol is irregularly absorbed from GIT= racemic warfarin Na completely absorbed orally, IM, IV = racemic warfarin Na completely absorbed orally, IM, IV

or rectally (diff preparations have diff rates of or rectally (diff preparations have diff rates of dissolution)dissolution)

= food dec rate but not extent of absorption= food dec rate but not extent of absorption= peak conc in plasma (oral) in 2-8 hrs = peak conc in plasma (oral) in 2-8 hrs → 99% bd to → 99% bd to

albumin → half life of IV bolu is 37 hrs → distributed in albumin → half life of IV bolu is 37 hrs → distributed in albumin space but not fd in milk unlike other coumarins albumin space but not fd in milk unlike other coumarins & indandiones → inactive metabolites by liver & kidneys & indandiones → inactive metabolites by liver & kidneys → excreted in urine & stool→ excreted in urine & stool

Toxic Effects:Toxic Effects:1. hemorrhage = ecchymoses hematuria, melena1. hemorrhage = ecchymoses hematuria, melena2. during pregnancy = birth defects, abortion2. during pregnancy = birth defects, abortion3. coumarin-induced skin necrosis3. coumarin-induced skin necrosis4. purple-toe syndrome (coumarin)4. purple-toe syndrome (coumarin)= antagonist is vit K (phytonadione)= antagonist is vit K (phytonadione)

4747

Drug Interactions:Drug Interactions: drug alters drug alters

1. Uptake or metbolism of other drugs1. Uptake or metbolism of other drugs2. synthesis, function or clearance of any factor 2. synthesis, function or clearance of any factor

or cell involved in hemostasis or fibrinolysisor cell involved in hemostasis or fibrinolysis3. The integrity of any epithelial surface3. The integrity of any epithelial surfaceEx: ASAEx: ASA

phenylbutazone, metronidazole, allopurinolphenylbutazone, metronidazole, allopurinol cimetidine = ↓ metabolism &/or displacement cimetidine = ↓ metabolism &/or displacement fromfrom

protein binding sitesprotein binding sites

Preparation:Preparation:1. Warfarin Na (COUMADIN, PANWARFARIN)1. Warfarin Na (COUMADIN, PANWARFARIN)2. Warfarin K (ATHROMBIN) 2. Warfarin K (ATHROMBIN)

4848

THROMBOLYTIC DRUGSTHROMBOLYTIC DRUGS

* PLASMIN = DIGESTS FIBRIN CLOTS * PLASMIN = DIGESTS FIBRIN CLOTS & OTHER PLASMA CHONs, INCLDG. & OTHER PLASMA CHONs, INCLDG. SEVERAL COAG. FACTORSSEVERAL COAG. FACTORS

* PLASMINOGEN = SINGLE-CHAIN * PLASMINOGEN = SINGLE-CHAIN GLYCOPROTEINGLYCOPROTEIN

* TISSUE PLASMIN ACTIVATOR (t-PA) = * TISSUE PLASMIN ACTIVATOR (t-PA) = BINDS TO FIBRIN AND CONVERTS BINDS TO FIBRIN AND CONVERTS PLASMINOGEN TO PLASMINPLASMINOGEN TO PLASMIN

= FROM ENDOTHELIAL CELLS = FROM ENDOTHELIAL CELLS

4949

1. STREPTOKINASE (KABIKINASE)1. STREPTOKINASE (KABIKINASE)

= 47-kDa PROTEIN PRODUCED BY = 47-kDa PROTEIN PRODUCED BY -HEMOLYTIC-HEMOLYTIC STREPTOCOCCUSSTREPTOCOCCUS= NO INTRINSIC ENZYMATIC ACTIVITY= NO INTRINSIC ENZYMATIC ACTIVITY= FORMS A STABLE, NOCOVALENT 1:1 COMPLEX W/ = FORMS A STABLE, NOCOVALENT 1:1 COMPLEX W/

PLASMINOGEN PLASMINOGEN CONFORMATIONAL CHANGE THAT EXPOSES CONFORMATIONAL CHANGE THAT EXPOSES ACTIVE SITE ON PLASMINOGEN THAT CLEAVES ARGININE 560 ACTIVE SITE ON PLASMINOGEN THAT CLEAVES ARGININE 560 ON FREE PLASMINOGEN MOLECULE TO FORM FREE PROTEINON FREE PLASMINOGEN MOLECULE TO FORM FREE PROTEIN

= LOADING DOSE GIVEN IV TO OVERCOME PLASMA= LOADING DOSE GIVEN IV TO OVERCOME PLASMA ANTIBODIES FORMED DURING PREVIOUS STREP.INFECTIONANTIBODIES FORMED DURING PREVIOUS STREP.INFECTION= HALF-LIFE IS 40-80 MINS= HALF-LIFE IS 40-80 MINS= ADVERSE EFFECTS: BLEEDING, ALLERGY, FEVER= ADVERSE EFFECTS: BLEEDING, ALLERGY, FEVER= A STREPTOKINASE-PLASMINOGEN COMPLEX, ANISTREPTASE = A STREPTOKINASE-PLASMINOGEN COMPLEX, ANISTREPTASE (EMINASE), IS USED FOR CORONARY THROMBOSIS(EMINASE), IS USED FOR CORONARY THROMBOSIS

5050

2. UROKINASE (ABBOKINASE)2. UROKINASE (ABBOKINASE)

= A 2-CHAIN SERINE PROTEASE CONTG.= A 2-CHAIN SERINE PROTEASE CONTG. 411 A. A.411 A. A.= FROM CULTURED HUMAN KIDNEY= FROM CULTURED HUMAN KIDNEY CELLSCELLS= HALF-LIFE OF 15-20 MINS. = HALF-LIFE OF 15-20 MINS. MET. IN MET. IN LIVERLIVER= LACKS FIBRIN & CONVERTS= LACKS FIBRIN & CONVERTS PLASMINOGEN TO PLASMINPLASMINOGEN TO PLASMIN= FROM ENDOTHELIAL CELLS SPECIFICTY= FROM ENDOTHELIAL CELLS SPECIFICTY SYSTEMIC LYTIC STATESYSTEMIC LYTIC STATE

5151

3. TISSUE PLASMINOGEN ACTIVATOR (t-PA)3. TISSUE PLASMINOGEN ACTIVATOR (t-PA)

= SERINE PROTEASE CONTG. 527 A. ACIDS= SERINE PROTEASE CONTG. 527 A. ACIDS

= POOR PLASMINOGEN ACTIVATOR W/O = POOR PLASMINOGEN ACTIVATOR W/O FIBRINFIBRIN

= PREFERENTIALLY ACTIVATES PLASMINOGEN = PREFERENTIALLY ACTIVATES PLASMINOGEN BOUND TO FIBRIN BOUND TO FIBRIN

FIBRINOLYSIS TO A THROMBUS AS IN FIBRINOLYSIS TO A THROMBUS AS IN ACUTE M. I. ( NO SYSTEMIC FIBRINOLYSIS)ACUTE M. I. ( NO SYSTEMIC FIBRINOLYSIS)

5252

HEMORRHAGIC TOXICITY OF THROMBOLYTIC HEMORRHAGIC TOXICITY OF THROMBOLYTIC TREATMENTTREATMENT

1. LYSIS OF FIBRIN IN “PHYSIOLOGIC THROMBI”1. LYSIS OF FIBRIN IN “PHYSIOLOGIC THROMBI”2. SYSTEMIC LYTIC STATE 2. SYSTEMIC LYTIC STATE SYSTMIC FORMATION OF SYSTMIC FORMATION OF

PLASMIN PLASMIN LYSIS OF OTHER COAGULATION LYSIS OF OTHER COAGULATION FACTORS (ESP. FACTORS V &VII)FACTORS (ESP. FACTORS V &VII)

CONTRAINDICATIONSCONTRAINDICATIONS1. SURGERY W/IN 10 DAYS1. SURGERY W/IN 10 DAYS2. SERIOUS GI BLEEDING W/IN 3 MONTHS2. SERIOUS GI BLEEDING W/IN 3 MONTHS3. Rx OF HPN (DP OF > 110 MM Hg)3. Rx OF HPN (DP OF > 110 MM Hg)4. ACTIVE BLEEDING OR HEMORRHAGIC DISORDER4. ACTIVE BLEEDING OR HEMORRHAGIC DISORDER5. PREVIOUS CVA OR ACTIVE INTRCRANIAL PROCESS5. PREVIOUS CVA OR ACTIVE INTRCRANIAL PROCESS6. AORTIC DISSECTION6. AORTIC DISSECTION7. ACUTE PERICARDITIS7. ACUTE PERICARDITIS

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ANTIPLATELET DRUGSANTIPLATELET DRUGS

1. ASPIRIN1. ASPIRIN = BLOCKS PRODUCTION OF THROMBOXANE A2 = BLOCKS PRODUCTION OF THROMBOXANE A2 BY INHIBITING (COX) – COMPLETE INACTIVATIONBY INHIBITING (COX) – COMPLETE INACTIVATION AT 160 MG OF ASA PER DAYAT 160 MG OF ASA PER DAY = MAXIMALLY EFFECTIVE AT 160-320 mg/DAY= MAXIMALLY EFFECTIVE AT 160-320 mg/DAY2. DIPYRIDAMOLE (PERSANTIN)2. DIPYRIDAMOLE (PERSANTIN) = A VASODILATOR; ALSO INTERFERES W/ PLATELET= A VASODILATOR; ALSO INTERFERES W/ PLATELET FORM. BY INCREASING CELLULAR CYCLIC AMPFORM. BY INCREASING CELLULAR CYCLIC AMP = W/ WARFARIN - INHIBITS EMBOLIZATION FROM = W/ WARFARIN - INHIBITS EMBOLIZATION FROM PROSTHETIC HEART VALVES (ONLY INDICATION)PROSTHETIC HEART VALVES (ONLY INDICATION) = W/ ASA - REDUCES THROMBOSIS IN THROMBOLIC= W/ ASA - REDUCES THROMBOSIS IN THROMBOLIC DISORDERSDISORDERS

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3. TICLOPIDINE ( TICLID)3. TICLOPIDINE ( TICLID) = THIENOPYRIDINE THAT INHIBITS PLATELET= THIENOPYRIDINE THAT INHIBITS PLATELET FUNCTION BYINHIBITING PLATELETFUNCTION BYINHIBITING PLATELET AGGREGATION & CLOT RETRACTIONAGGREGATION & CLOT RETRACTION = USED IN PREVENTION OF THROMBOSIS IN= USED IN PREVENTION OF THROMBOSIS IN CEREBRAL VASCULAR & CORONARY ART. DISEASECEREBRAL VASCULAR & CORONARY ART. DISEASE

4. CLOPIDOGREL (PLAVIX)4. CLOPIDOGREL (PLAVIX) = THIENOPYRIDINE SIMILAR TO TICLOPIDINE BUT= THIENOPYRIDINE SIMILAR TO TICLOPIDINE BUT LESS TOXIC (LESS USE SO ?)LESS TOXIC (LESS USE SO ?) = PRODRUG W/ SLOW ONSET OF ACTION= PRODRUG W/ SLOW ONSET OF ACTION = EQUAL TO ASA IN 2= EQUAL TO ASA IN 2 PREVENTION OF STROKE PREVENTION OF STROKE

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5. GLYCOPROTEIN IIb/IIIA INHIBITORS5. GLYCOPROTEIN IIb/IIIA INHIBITORS = INHIBIT THE PLATELET RECEPTOR= INHIBIT THE PLATELET RECEPTOR

(PLATELET INTEGRIN) GYLCOPROTEIN IIb/IIIa (PLATELET INTEGRIN) GYLCOPROTEIN IIb/IIIa = (DESIGNATED AS = (DESIGNATED AS IIbIIb3) FROM BINDING W/3) FROM BINDING W/ FIBRINOGEN & VON WILLEBRAND FACTOR, W/C FIBRINOGEN & VON WILLEBRAND FACTOR, W/C ANCHOR PLATELETS TO FOREIGN SURFACES & TOANCHOR PLATELETS TO FOREIGN SURFACES & TO EACH OTHER, THEREBY MEDIATING AGGREGATIONEACH OTHER, THEREBY MEDIATING AGGREGATION= THE RECEPTOR IS ACTIVATED BY PLATELET= THE RECEPTOR IS ACTIVATED BY PLATELET AGONISTS SUCH AS THROMBIN, COLLAGEN, OR AGONISTS SUCH AS THROMBIN, COLLAGEN, OR THROMBOXANE A2 TO DEVELOP BINDING SITES THROMBOXANE A2 TO DEVELOP BINDING SITES FOR ITS LIGANDS, W/C DO NOT BIND TO RESTING FOR ITS LIGANDS, W/C DO NOT BIND TO RESTING PLATELETSPLATELETS

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5.1 ABCIXIMAB (REOPRO5.1 ABCIXIMAB (REOPRO))

= FAB FRAGMENT OF A HUMANIZED= FAB FRAGMENT OF A HUMANIZED MONOCLONAL AB AGAINST THE RECEPTOR;MONOCLONAL AB AGAINST THE RECEPTOR; ALSO BINDS TO VITRONECTIN RECEPTOR ONALSO BINDS TO VITRONECTIN RECEPTOR ON PLATELETS, VASCULAR ENDOTHELIAL CELLS PLATELETS, VASCULAR ENDOTHELIAL CELLS AND SMOOTH MUSCLE CELLS AND SMOOTH MUSCLE CELLS = USED IN CONJUNCTION W/ PERCUTANEOUS = USED IN CONJUNCTION W/ PERCUTANEOUS ANGIOPLASTY FOR CORONARY THROMBOSESANGIOPLASTY FOR CORONARY THROMBOSES = HALF LIFE OF 30 MINS= HALF LIFE OF 30 MINS = MAJOR ADVERSE EFFECT IS BLEEDING= MAJOR ADVERSE EFFECT IS BLEEDING

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5.2 EPTIFIBATIDE (INTEGRILIN)5.2 EPTIFIBATIDE (INTEGRILIN)

= BLOCKS PLATELET= BLOCKS PLATELET

AGGREGATION IN VITROAGGREGATION IN VITRO

AFTER IV INFUSION INTO PATIENTSAFTER IV INFUSION INTO PATIENTS

= IN UNSTABLE ANGINA & FOR = IN UNSTABLE ANGINA & FOR

ANGIOPLASTIC CORONARYANGIOPLASTIC CORONARY

INTERVENTIONSINTERVENTIONS

= ADVERSE EFFECT IS BLEEDING= ADVERSE EFFECT IS BLEEDING

5.3 TIROFIBAN (AGGRASTAT)5.3 TIROFIBAN (AGGRASTAT)

= EFFICACY IN NON-Q-WAVE MI & = EFFICACY IN NON-Q-WAVE MI &

UNSTABLE ANGINAUNSTABLE ANGINA

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THERAPEUTIC USES OF THERAPEUTIC USES OF ANTICOAGULANTS, THROMBOLYTIC & ANTICOAGULANTS, THROMBOLYTIC &

ANTIPLATELET DRUGSANTIPLATELET DRUGS

PRINCIPLES:PRINCIPLES: SLOWING THE RATE OF FIBRIN SLOWING THE RATE OF FIBRIN

FORMATIONFORMATION INHIBITION OF PLATELET FUNCTIONINHIBITION OF PLATELET FUNCTION ACTIVATION OF FIBRINOLYTIC ACTIVATION OF FIBRINOLYTIC

MECHANISMMECHANISM

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INDICATIONS:INDICATIONS:

1. VENOUS THROMBOEMBOLISM1. VENOUS THROMBOEMBOLISM2. MYOCARDIAL INFARCTION2. MYOCARDIAL INFARCTION3. UNSTABLE ANGINA - ASA3. UNSTABLE ANGINA - ASA4. SAPHENOUS VEIN BYPASS GRAFTS4. SAPHENOUS VEIN BYPASS GRAFTS5. PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY5. PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY6. ATRIAL FIBRILLATION6. ATRIAL FIBRILLATION7. PROSTHETIC HEART VALVE7. PROSTHETIC HEART VALVE8. VALVULAR HEART DISEASE8. VALVULAR HEART DISEASE9. CARDIOVASCULAR DISEASE9. CARDIOVASCULAR DISEASE10. PERIPHERAL VASCULAR DISEASE10. PERIPHERAL VASCULAR DISEASE11. 111. 1 & 2 & 2 PREVENTION OF ARTERIAL THROMBOEMBOLISM PREVENTION OF ARTERIAL THROMBOEMBOLISM12. MISCELLANEOUS - PREVENT OCCLUSION OF12. MISCELLANEOUS - PREVENT OCCLUSION OF EXTRACORPOREAL DEVICES (DIALYSIS)EXTRACORPOREAL DEVICES (DIALYSIS)

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