Antiplatelet Agents (Antithrombotics) #G3FR_28

Agents used to inhibit platelet aggregation preventing intravascular thrombosis. This effect can be measured by bleeding time prolongation
Factors that increase platelet aggregation Factors that decrease platelet aggregation
1- Thromboxane A2 (TXA2 = platelet PG) 1- PGI2 (prostacyclin) !"cAMP
2- ADP ! Activation of glycoprotein receptors (GP) IIb/IIIa 2- "cAMP & cGMP !#Ca+2 !# Thromboxane A2
3- Serotonin & platelet aggregation factor (PAF)
Ticlopidine,Clopidogrel Abciximab Ebtifibatide Tirofiban Dipyridamole Pentoxyphylline Aspirin Sulphinpyrazone Ketanserin
+,- . 6789 :;<=>?=@:?
• Irreversibly block ADP • Monoclonal antibody Block GP IIb/IIIa receptor 1. Phosphodiesterase inhibitor !"cAMP & cGMP !"#$ℎ&'()&$ #$&' /⎯⎯1 23 42/⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯1 AB!2 selective serotonin
receptors on platelet membrane against GP IIb/IIIa !#intracellular Ca+2 !#TXA2 synthesis & (5-HT2) antagonist !
MOA receptor ! block the platelet aggregation #platelet aggregation
binding of fibrinogen A cyclic peptide • not a 2. #adenosine uptake. 2. Restores flexibility • irreversible • inhibits COX & VD
preventing platelet analogue to the Peptide 3. potentiate effect of of RBCs membrane acetylation of (COX-1) !#platelet PG
aggregation. terminal chain of analogue prostacyclin on platelets. 3. # Fibrinogen in • Aspirin (75- 150 mg) synthesis !#platelets
fibrinogen which bind i.e. Non- blood !# blood inhibits thromboxane aggregation
to IIb/IIIa receptor. competitive viscosity A2 synthetase enzyme. • Uricosuric agent
i.e. competitive blocker
blocker
.
• well orally • Its antiplatelet effects • Given by IV infusion on only Nitrates
(Food # ticlopidine absorption) persist for 24-48 hrs after When the infarction is stopped Release of NO !"
P/K • highly PPB cessation of infusion • rapidly cleared by kidney so persist soluble guanylate
• hepatic metabolism to active for only for 4 hrs after cessation cyclase (sGC) !"
metabolites (So slow onset 3-5 • excreted by kidney cGMP !# platelets
days) aggregation & VD
• renal and fecal elimination
SE • Ticlopidine: BMD • Expensive (limits its Bleeding - Abdominal pain - Gastric upset Nifedipine
(Neutropenia, agranulocytosis, use) - Headache & Dizziness - Anemia +2
Ca channel blocker.
thrombocytopenia & aplastic • Potential of bleeding - Skin rash - Leucopenia
anemia especially with
• Clopidogrel better !less BMD anticoagulants.
• Expensive.
• Slow onset (3-5 days)
• Diarrhea.
• Prolonged bleeding
(no antidotes are available)
DI • enzyme inhibitors (CYP450) ! Cilostazol Dazoxiben Epoprostenol Heparin
# metabolism of phenytoin, a newer PDE-1 used for intermittent claudication selective inhibitor of • PGI2 analogue !
tolbutamide, warfarin, Dextran
promotes vasodilation and inhibits platelet TXA2 synthetase VD
Fluvastatin and tamoxifen if aggregation. enzyme • IVI !very short t1/2 Clofibrate
taken concomitantly
• Clopidogrel is preferred in • ineffective alone but • Intermittent • Rheumatic valvular hypocholesterolemic
ischemic heart diseases: used with: claudication diseases !#incidence agent
- Unstable angina - aspirin prevent (peripheral vascular of embolism
- Acute myocardial infarction cerebrovascular ischemia disease)
- Transient ischemic attacks - warfarin for inhibiting
USES - Stroke • IVI with heparin for: thrombo-embolism in
- Acute coronary • Acute coronary syndrome !# patients with prosthetic
syndromes incidence of thrombotic complication heart valves.
- Percutaneous • vasodilator for angina.
coronary Intervention

Uses of Antiplatelets
1- Cerebrovascular disorders: a. Transient ischemic attacks (TIA). b. 2ry prevention in cerebrovascular diseases. c. Strokes.
2- Acute coronary syndrome. 3- Percutaneous coronary intervention with or without stent. 4- Coronary artery bypass graft.
 Fibrinolytic Drugs (Thrombolytics) #G3FR_29
Blood coagulation Fibrinolysis Fibrinolytics
• conversion of soluble fibrinogen to insoluble fibrin by the enzyme thrombin. Means fibrin degradation by specific enzyme plasmin. Agents used to lyse recently developed thrombus (< 6 hours) and are given by
• Several circulating proteins interact in a cascading series of reactions leading intravenous, intraarterial & intracoronary injection.
to formation of thrombin which has a central role in hemostasis.
Therapeutic uses in thromboembolic disorders include Contraindications Control of thromboembolic disorders
1- Acute myocardial infarction. 2- Acute ischemic stroke. - Patients with healing wounds - Pregnancy - Bleeding tendency. 1- Inhibitors of platelets aggregation used to prevent thrombus formation.
3- Peripheral arterial thrombosis. 4- Pulmonary embolism. - History of Cerebrovascular accidents - Metastatic Cancer 2- Thrombolytics used to dissolve already formed thrombus.
6- Catheter restoring and shunt function by lysing clot causing occlusion. 3- Anticoagulants used to prevent thrombus formation and extension of the
2- Deep venous thrombosis. present thrombus.
1- Streptokinase 2- Anistreplase 3- Urokinase 4- Alteplase 5- Tenecteplase 6- Reteplase
Source • Obtained from hemolytic streptococci • Derivative of streptokinase • It is human enzyme obtained from • Tissue plasminogen activator (t-PA) originally derived • Mutant of t-PA with
! antigenic + lyse-plasminogen tissue culture of human kidney cell or from cultured human melanoma cell. longer duration
• the complex has thrombolytic urine. • Now it is a product of recombinant DNA technology
activity ! Not antigenic
MOA • Streptokinase has no enzymic activity. • The drug is inactive (the • Directly converts plasminogen to • Selective activation of plasminogen bound to fibrin
• combined with plasminogen (pro- catalytic site is blocked by P- active plasmin. clot ! no systemic fibrinolysis ! less risk of bleeding
activator) ! complex ! activation anisoyl group). MNOPQRSTU • Low affinity for free plasminogen in plasma
Plasminogen /⎯⎯⎯⎯⎯⎯1 active plasmin.
plasminogen to plasmin ! hydrolyses • It is activated by spontaneous
fibrin plugs hydrolysis of the P-anisoyl
• The complex also catalyzes the clotting group after IV injection
factors V and VII ! general fibrinolytic • If not given within 30 min of
state dissolution, it should be
discarded.
Why Anistreplase is better than streptokinase Advantage
Streptokinase in blood ! forms complex Anistreplase Complex of 1- Not antigenic. 1. Not antigenic. - longer duration - Less expensive
with glu-plasmainogen ! activates streptokinase and lyse- 2- Direct activator. 2. Selective to fibrin clots (No systemic fibrolysis) - More fibrin specific
plasminogen (both bound to fibrin & plasminogen ! activates 3- Does not produce hypotension. 3. Superior in dissolving older clots. than alteplase.
fibrinogen) ! higher risk of bleeding plasminogen-bound to fibrin 4. At low doses ! More effective.
! less risk of bleeding 5. Act Rapidly.
Side effect Disadvantage
l - Bleeding (it is not fibrin-specific). - Expensive 1. Expensive. - Less fibrin-specific
2- Hypersensitivity: rash, fever, - Not fibrin specific (may cause 2. by increasing doses ! loses selectivity (may cause
anaphylaxis (hypotension) and therapeutic bleeding) bleeding)
failure
Dose 1.5 million units in 200 ml saline IV Total dose of 0.9 mg/Kg (10% is given as IV bolus and Given I.V. bolus,
infusion over 1-hour, single dose the reminder is given by IV infusion over 60 minutes)
Uses 1. Acute myocardial infarction.
3. Acute ischemic stroke (within 3 hours of its onset).
2. Massive Pulmonary embolism.
 Blood Coagulation #G3FR_30
Functions of thrombin Endogenous anticoagulants
1- Generation of fibrin. 2- Thrombin is a potent platelet activator. 3- Exerts anticoagulant effect by activating protein C pathway. 1- Antithrombin: an α-globulin ! inactivates coagulating factors (IIa, IXa, Xa).
4- Activation of clotting factors ! more thrombin generation. 5- Activates factor XIII (fibrin stabilizing factor) !stabilize the clot. 2- Protein C & S: glycoproteins synthesized by liver cells ! inactivate factors Va & VIIIa ).
Anticoagulant Drugs
I) Interfere with synthesis of coagulation factor II) Inhibit action of coagulation factors
Vitamin K antagonist A- Thrombin inhibitor B-Thrombin-like
1- Indirect By activation of endogenous antithrombin 2- Direct Binds to thrombin Ancord
!#" warfarin Heparin (HMW or Unfractionated) A- Parenteral Drug
Source Plant origin (now it is synthetic) • Animal origin as a macromolecule complexed with histamine in mast cells and basophils in lung, liver and intestine 1- Lepirudin .snake venoum
• Commercial preparations are derived from bovine lung and porcine intestinal mucosa enzyme
Chemistry Coumarin derivative • sulphated mucopolysaccharides with HMW (8000 + 30000) - Prepared by rDNA technology from MOA
• Strong acidic drug, negatively charged ! combine with positively charged protein of blood coagulation factors hirudin (from leech saliva)
Abs • Well orally (100% bioavailability) ! delayed onset 1-2 days and long duration of action 2-3 days • Not orally (given IV & SC). - IV: immediate anticoagulant effect & t1/2 = 1.5 hours, short duration (4-6h). - Irreversible thrombin inhibitor: • Thrombin-like !
- SC: anticoagulant effect occurs within l -2h - It acts independent on antithrombin Promotes conversion
Dis • Highly PPB to albumin (about 96%) small vd • Crosses BBB and placental barrier (teratogenic). • highly hound to +ve charged plasma proteins. • Not BBB or placenta barrier • Distributed intravascular (small Vd), - Like heparin: • Monitored by PTT. of fibrinogen to
Met • Metabolized slowly in liver (CYP450) to inactive metabolites • 80 % metabolized in liver by heparinase enzyme ! inactive uroheparin • Cause Bleeding abnormal fibrin that
Exc • Excreted in urine. stool and excreted in milk • Long t1/2: about 63 hours. • 20% excreted as such in urine • Not excreted in milk. -little effect on platelet & bleeding time rapidly broken by
MOA Warfarin inhibits vitamin K epoxide reductase enzyme ! inhibition of hepatic synthesis of vitamin 1- It binds to antithrombin through a unique pentasaccharide sequence. 2- " antithrombin activity (l000 times) . normal fibrinolytic
- Replaces heparin in patients with
K-dependent dotting factors (II. VII. IX. X). 3- Heparin serves as a catalytic template for the interaction of antithrombin and activated coagulation factors system and
(heparin is catalyst or cofactor) without being consumed and released intact for new binding to more antithrombin. heparin induced thrombocytopenia.
Actions 1. Anticoagulants (only in-vivo). 2. Hepatic synthesis of protein C & S (natural anticoagulants). 1- Anticoagulant in vivo and in vitro. 2- Inhibits platelet aggregation. - Excreted by kidney So ! Used With phagocytosed by
3. Rodenticide. 3- Lipaemic cleaning action by activation of lipoprotein lipase !"hydrolysis of TG to fatty acids after fatty meals. great caution in patients with renal RES ! depletion of
I. ttt of thromboembolic diseases: 1- CVS: - After coronary angioplasty and stent - Pulmonary embolism. 2- CNS: stroke, cerebral thrombosis impairment as there is no antidote). fibrinogen.
Uses - MI to reduce coronary re-thrombosis after thrombolytic ttt - DVT: “Acute deep venous thrombosis”
II. Prophylaxis: 1. thromboembolic complications of AF or cardiac valve replacement. II. Prophylaxis:1. Prevent thromboembolic complications of surgery 2- Argatroban Adverse effect
2. Prevent clotting during blood transfusion & hemodialysis
1- Allergy. 1- Allergy 3- Alopecia & Transient loss of hair 3- Bleeding. 4- oSteoporosis. 6- Thrombosis. - Small molecule thrombin inhibitor. - Hemorrhage
2- Anorexia, vomiting. 5- Hyperkalemia (due to decreased synthesis of aldosterone) - Metabolized in liver. - Hypersensitivity
SE 3- Bleeding: ttt by stopping the drug and giving vitamin K & fresh Blood transfusion. 7- Thrombocytopenia. Heparin-induced thrombocytopenia (HIT): 2 types: - IVI, Short t1/2
‫اﺑﺴﻂ‬ 4- Sudden stop ! rebound thromboembolic manifestations. a. Mild or transient (onset I- 5 days) due to nun- immunological reaction - Monitored by PTT.
b. Severe & persistent (onset 5- 14 days) due to immunologic reaction ! platelet destruction & release of contents
Antidote
5- Teratogenicity. - used in: coronary angioplasty in - fibrinogen or
! thrombosis. So, Platelet count # by 50% & develop thromboembolic complications
Treatment: Stop heparin and give Lepirudin or Fondaparinux.
patient with HIT - anti -venom
1- Allergy. 2- Active TB. 3- Abortion 4- Advanced Hepatic or renal disease. 5- Peptic ulcer & ulcerative colitis 3- Bivalirudin
CI 6- CVS: subacute bacterial endocarditis & severe hypertension. 7- CNS: intracranial hemorrhage, recent surgery in brain eye and spinal cord & lumbar puncture or spinal anesthesia. 8- Cancer of Viscera. - Bivalent thrombin inhibitor
9- HIT “Only heparin”. 10- Hemophilia & purpura 11- Never given IM to avoid Haematoma.
- Inhibit platelet activation
Dose Initial oral dose of 10 mg for 2 days, then maintenance dose of 2-10 mg/ day. • Intermittent IV dosing 5000 units/4 hours.
• IV infusion ! IV bolus dose of 5000-10.000 units. then 1000 unit/hour infusion for 7-10 days.
- IV (rapid onset & offset, short T1/2)
• Prophylactic: as 5000 units/ 8 hours SC. - 20 % renal clearance and 80% hepatic
Control of - by prothrombin time (PT) prolonged up to 2 times normal (12- 15 seconds). 1- Coagulation time = whole blood clotting time (WBCT): normally 5-7 min, prolonged to 2-2.5 times - Used in: Percutaneous coronary
dose cNOdeNOfgQR dQfU Oh cSdQURd
2- Activated partial thromboplastin time (aPTT): normally 26-33 seconds, prolonged to 2-2.5 times angioplasty
- PT is expressed in INR. = International Normalized Ratio "INR" = TdSRiSNi cNOdeNOfgQR dQfU
Antidote Vitamin K 50- 100 mg IV. Protamine sulphate slowly IV 1mg for each 100-unit heparin for neutralization
N.B. excess protamine may cause bleeding because it has a weak anticoagulant action
Drug interactions of warfarin Low molecular weight heparin LMWH Fondaparinux Rivaroxiban B- Oral Drug
I) Drugs that increase warfarin anticoagulant effect II) Drugs that decrease anticoagulant effect of Enoxaparin, dalteparin (MW 6000-8000) synthetic pentasaccharide Dabigatran
!must decrease the dose of warfarin to prevent bleeding warfarin ! Must increase the dose of warfarin to MOA • The same as unfractionated heparin binds to and increases The first oral factor Xa - Equivalent efficacy & safety as
1- Broad spectrum antimicrobials e.g. tetracyclines & obtain its therapeutic effects
cephalosporins !#synthesis of vit K by intestinal flora. 1. " Vitamin K intake in green leafy vegetable. activity of antithrombin • selectively inhibits activated factor Xa inhibitor LMWH
2- Some cephalosporins (cefoperazone, cefoperazone, 2. # Absorption of warfarin e.g. cholestyramine, Advantages 1- Equal efficacy as HMWH. Used in ttt of: - No routine monitoring is required
cefamandole & Cefaclor) have warfarin-like effects. antacid Al(OH)3 gel and sucralfate 2- Less incidence of bleeding. 3- Longer T1/2 (single daily dose). - deep venous thrombosis - used for: prophylaxis in
2. Liquid paraffin !#absorption of vitamin K. 3. Hepatic enzyme inducers e.g. rifampicin, ‫ﺲ‬ ‫ﺒ‬‫ﻟ‬‫ا‬ 4- Less need for dose monitoring (# nursing time and costs) - prevention of stroke in hip or knee replacement surgery to
4. Displacement from PPB sites e.g. phenylbutazone, phenobarbitone, carbamazepine, phenytoin & nicotine. 5- Predictable therapeutic effects atrial fibrillation prevent thromboembolic
sulfonamides. indomethacin, aspirin and clofibrate 4. Estrogens !"synthesis of some vitamin K- 6- Predictable P/K profile (t1/2 = 4 h & bioavailability 90% )
• Aspirin has antiplatelet effect & with LD has warfarin- dependent clotting factors and synthesis of 7- S.C on patient weight adjusted basis (easy calculation of dose).
like effect hypoprothrombinemia (synergistic effect). antithrombin i.e. antagonize warfarin. 8- Can be used easily for inpatient and outpatient therapy.
• Clofibrate has antiplatelet effect & enzyme inhibitor. 5. Diseases: hypothyroidism !#BMR !# N.B. • LMWH is CI in cases of •Not cause
5. Hepatic enzyme inhibitors as cimetidine, allopurinol, metabolism of already formed clotting factors increased bleeding risk & HIT. thrombocytopenia
chloramphenicol, ciprofloxacin, erythromycin, III) safe drugs with warfarin: • In bleeding due to LMWH • Eliminated unchanged in
Sulfonamides, Metronidazole and Azole antifungals. 1- Paracetamol & Penicillins. overdose, protamine reversal is urine (not used in renal
6. Drugs that inhibit platelet aggregation: NSAIDs 3- Na valproate & Clonazepam. only partial. impairment) .
7. Diseases: Liver diseases & hyperthyroidism ("BMR) 4- Lignocaine, Disopyramide & Atropine • Longer t1/2 = 17- 21 h
5- Progestin only CCP are preferred with warfarin • SE ! bleeding
Other anticoagulants similar to warfarin Unfractionated heparin LMWH
1-Dicoumarol 2- Indandione derivatives Anti -platelet action ++++ ++
- Synthetic coumarin derivative, Phenindione & Diphenadione Selectivity Less selective (equal efficacy More selective on activated factor Xa
- present in plants like warfarin. inactivation of factors Ila & Xa)
- Like warfarin in P/K and P/K but weaker by 1: 40. - Similar to warfarin PTT monitoring Required Not required
- More toxic than warfarin: not suitable for prolonged use - More hepatic & renal toxicity t1/2 Short (50-90 minutes) Long (2-5 times longer)
 Warfarin Heparin #G3FR_31
Route Oral Parental (not IM)
Site of action Liver Blood
(effective only in vivo) (effective on both vivo & in vitro)
Onset Delayed (2-3 day) Immediate
Duration of action Long (2-5 day) Short (4 h)
MOA Inhibit synthesis of vitamin K-dependent Potentiate action of anti-thrombin !
dotting factors inhibit activated clotting factor
Lab control of dose PT & INR PPT
Antidote Vitamin K Protamine sulphate
Fresh plasma transfusion
Safety with pregnancy No Yes

Some agents are used in-vitro as anticoagulants that interfere with ionized Ca 2+
a. by precipitation e.g. Na+, K+ oxalate in test tubes for blood samples.
b. by deionization (combine with ionized Ca 2+ without precipitation) e.g. Na+ or K+ citrate or Na+ edetate used in
test tubes for blood samples or in blood banks for blood transfusion.
 Drug therapy of anemia #G3FR_32
Anemia means reduction of hemoglobin level in blood below normal level (14- 16 gm/ dl in males & 12- 14 gm/ dl in females).
Types of anemia
Iron deficiency anemia Pernicious anemia Megaloblastic anemia Aplastic anemia
1. # Iron intake. - Absence of intrinsic factor (glycoprotein Nutritional due to deficiency of folic acid • Analgesic antipyretics: pyrazolone derivativ
2. Malabsorption. secreted by parietal cells that is required for abs • Antirheumatics: Gold therapy.
3." Requirements e.g. pregnancy & children. of Vit B12 e.g. achlorhydria & gastrectomy • Antithyroid: propyl thiouracil.
Cause 4. Chronic blood loss (excessive menstruation or parasite e.g. ankylostoma & Ascaris) Manifestation • Antiepileptics.
1- Blood: macrocytic anemia 2- GIT: stomatitis, glossitis lead to beefed tongue due to defective epithelization • Antimicrobial: chloramphenicol.
3- Neurological: peripheral neuritis with spinal cord • Cytotoxic drugs.
affection due to myeline degeneration.
Iron Vitamin B12 Folic acid Manifestation
Total body iron = 3-5 mg (2/3 in heamoglobin & 1/3 is stored) Extrinsic factor & anti-pernicious anemia factor. - Folic acid found in yeast, liver, fresh - Pancytopenia: Agranulocytosis
1- Daily requirements: males 1mg & females 2-3 mg) that "in anemia, pregnancy & children. Absorption: green vegetables and fruits in conjugated - Early sign is sore throat & fever
2- Only 10% of ingested iron is absorbed in normal person while anemic patient & pregnant women
B12 + intrinsic factor “from gastric parietal cell” inactive form. - confirmed by complete blood picture CBC
can absorb up to 30%.
qrs & uv6 r ! absorbed from ileum by pinocytosis. }Qd ~.9 Treatment
3- Fekl (no""&$) /⎯⎯⎯⎯⎯⎯⎯⎯1 Fek9 (no""(wx) ! absorbed in duodenum Distribution: transported to BM by: Conjugated folic acid /⎯⎯⎯⎯1 free folic acid
4- ferrous (in duodenal mucosa) ! Ferric + apoferritin ! ferritin. 1- Stop causative drug.
}Qd ~.9 k }Qd •
5- ferritin is transported in blood by transferrin (transport globulin) to RES
• Mainly by transcobalamin II (β-globulin). ÄqÅÇ É< Ñ?ÖÑ<ÖÜ 2- Fresh blood transfusion.
• Less by transcobalamin I (α-globulin) /⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯1 folinic acid
( BM, liver, spleen & kidney ) & stored as ferritin 3- Give penicillin.
P/K Storage: liver and kidney - Folinic acid act as coenzyme in synthesis
6- Saturation of tissue stores ! saturation of blood transferrin ! saturation of mucosal ferritin ! 4. Give vitamin B12 + folic acid.
mucosal block ! no more absorption of oral iron. Excretion: • Bile (enterohepatic cycle). of purine base, DNA, and erythropoiesis. 5- Cortisol
7- Iron is excreted via desquamation of epithelium of skin and GIT mucosal shedding. • Urine (0.25μg/ day). 6 anabolic.
Factors affecting absorption - Daily requirements of folic acid are about 7- Hemopoietic growth factor: erythropoietin
1- " Iron absorption 2- # Iron absorption Drugs that decrease Vit B12 absorption 50μg that increase during pregnancy. granulocyte colony stimulating factor
1. Pregnancy & Iron-deficiency anemia. 1- Achlorhydria, Antacids, tannic Acid, - Neomycin. - PASA,
2. HCL, ascorbic acid (vitamin C), 2- Phytates, Phosphates, Oxalate, - Metformin - Colchicine.
succinates & glutathione reduce Fe ! Fe
+3 2+
3- Ca2+, Tetracyclines
3. Amino acids (meat factor) and fructose. 4- Desferrioxamine
1- Iron-deficiency anemia. 1- Pernicious anemia. 2- Neuropathies. 1- Megaloblastic anemia due to Hemolytic anemia
2- Prophylaxis to prevent iron-deficiency anemia in: 3- Lipotropic in hepatic diseases. malnutrition or malabsorption.
Uses e.g. for drug-induced hemolytic anemia:
• Pregnancy. • Premature infants. 4- malabsorption & gastrectomy !Replacement 2- Increase requirements during pregnancy.
1- Antigenic: methyl dopa.
• Children. 5- Prophylactic with drugs that #absorption of 3- In pernicious anemia must be given with
2- Direct effect: lead.
• During ttt of pernicious anemia with vit B12 (iron deficiency may occur due to rapid Vit B12 vitamin B12. It is contraindicated give folic 3- Idiosyncrasy: favism G6PD deficiency.
blood formation). N.B. Iron is contraindicated in haemolytic anemia. 6- Cyanide poisoning (Hydroxycobolamine) acid alone in pernicious anemia because it
e.g. sulfonamides, primaquine, aspirin, beans.
depletes Vit B12 in it activation so worsens
Preparation
neurological manifestation Methemoglobinemia
Oral Parenteral 1- Cyanocobalamin IM in pernicious anemia 1000μg /
- Ferrous sulphate 300 mg tds (highly irritant) 1- Iron dextran 50 mg/ml deep IM or IV day for 2 weak to fill stores then l000 μg/ month for life. 4- Chronic use of antiepileptic (phenytoin)
2- Hydroxycobolamine IM (more bound to tissue to correct associated macrocytic anemia. Causes
- Ferrous gluconate 300 mg tds 2- Iron sorbitol citric acid complex 50 mg/ml
- Ferrous fumarate 200 mg tds deep IM only. DOC due to: proteins. So more retained in the body for long period. 5- With drug that #DHF reductase ! Nitrites, phenacetin, primaquine,
- Iron choline citrate (least irritant) for children. - Rapidly absorbed. Used in pernicious anemia & cyanide poisoning trimethoprim, pyrimethamine, proguanil, sulfonamides and CO ! Hb-Fe3+
• Oral iron is given for 2 months to reach normal - Stored in bone marrow and liver. 3- Liver extract: IM injection may cause allergy. methotrexate (better use folinic acid) Treatment
Hb level and for another 2 months to fill stores - Highly bound to transferrin. 4- Vitamin B12 concentrate: sublingual - Reducing agents e.g. ascorbic acid
1- GIT upset: nausea, vomiting, hyperacidity and A. Local: Functions of vitamin B12 Dose: 10 - 20 1ng/ day orally. - vitamin C & methylene blue 1 %.196
constipation. - IM ! Pain, pigmentation & inflammation 1- Essential for hemopoiesis.
2- black discoloration of: - I.V ! Thrombophlebitis
- teeth (form iron sulphide “oral solution”) B. Systemic:
2- Maturation of epithelial cells.
- stool 1- Metallic taste, headache, fever, & hemolysis. 3- Myelination of nerve fibers and neuronal
SE 3- Acute oral iron toxicity: 2- Muscle and joint pain. functions.
a. Sever GIT irritation: abdominal pain, nausea, 3- Hypersensitivity (bronchospasm & skin rash). 4- Has lipotropic action in liver.
vomiting, hematemesis & black or bloody diarrhea 4- Generalized lymphadenopathy.
b. Systemic: acidosis, CVS collapse, coma. and 5- In toxicity:
death especially in children from brain damage - CVS :(hypotension, tachycardia and fainting)
- CNS: (encephalopathy and convulsions).
Treatment of acute oral toxicity Treatment of parenteral toxicity
1- Ingest raw egg milk. 1- Desferrioxamine
2- Gastric Lavage with NaHCO3 & deferoxamine 2- symptomatic treatment
3- Desferrioxamine IM, IVI or in Lavage
4- Fluids dehydration & hypotension
5- NaHCO3 IV infusion to correct acidosis.
 Hematopoietic growth factors #G3FR_33
They control the proliferation and differentiation of stem cells of bone marrow.
Drugs used to treat bone marrow failure
1- Epoietin alfa & Darbipoietin 2- Sargramostim 3- Filgrastim & Pegfilgrastim 4- Oprelvekin
MOA • Recombinant form of Erythropoietin. • Recombinant granulocyte-macrophage • Recombinant granulocyte colony-stimulating factor • Recombinant human interleukin II (IL-II).
• A glycoprotein that stimulates RBCs production. colony-stimulating factor (GM-CSF). (G-CSF). • Promotes proliferation of megakaryocyte
• Normally produced by the kidney. !"platelet formation
USES a. Chronic renal failure. a. Promote bone marrow recovery in patient a. Prevent & treat chemotherapy-induced neutropenia • prevent and treat chemotherapy-induced
b. With cancer chemotherapy. undergoing bone marrow transplantation b. Promote bone marrow recovery in patient thrombocytopenia
c. Patients with acquired immune deficiency: b. Promote bone marrow recovery after undergoing bone marrow transplantation.
syndrome (AIDS) cancer chemotherapy. • Pegfilgrastim has longer duration of action than
d. illegal by athletes (it enhances performance) c. Treat drug- induced BM depression. filgrastim

Control of Bleeding
A) Local hemostatic B) Systemic coagulants
l. Physical methods: pressure, cold & cautery. l. Fresh blood transfusion: restore volume and supply
2. Vasoconstrictors: adrenaline in nasal pack in epistaxis. coagulation factors
3. Sclerosing agents: Irritant substances induce venous 2. Thromboplastin IM (coagulen).
thrombosis 3. With capillary fragility:
• e.g.: a. Ethanolamine oleates. a. Vitamin C (ascorbic acid) + rutin to treat scurvy.
b. Phenol derivatives. b. Ethamsylate orally & injection.
c. Na salt of fatty acids e.g. Na morrhuate, Na Linoleate. 4. Anti-hemophilic globin (factor VIII) ! haemophilia.
• Uses: esophageal varices, leg veins or piles 5. In fibrinolytic overdose: use antifibrinolytics.
4. Local coagulants: • Aminocaproic acid & taneexamic acid (synthetic, orally
a. Thromboplastin: (mammalian ! used topically & IM) active, excreted in urine).
b. Thrombin powder • MOA: Competitive antagonists of fibrinolytic activator i.e.
c. Human fibrin foam (sponge). stop plasminogen activation & plasmin formation
d. Fibrin glue: human fibrinogen + human thrombin. • uses: control bleeding with overdose or of fibrinolytics
e Oxycel (oxidized cellulose): sticky mechanical blockage & clot • Adverse effect: intravascular thrombosis.
formation. 6- In anticoagulant therapy: • If warfarin ! use Vit k
• If heparin !protamine sulphate.
Vitamin K
Preparations of vitamin K
l. Vitamin K-1 2. Vitamin K-2 3. Vitamin K-3
Phytonadione Menaquinone Menadione
- Natural of plant origin. - Natural synthesized by flora, - Synthetic
- Fat soluble so needs bile for abs - Fat soluble so needs bile for abs. - water-soluble salt. no need for bile salts.
- IM and IV used in emergency - displaces bilirubin in neonates !Jaundice
and kernicterus
Therapeutic uses of vitamin K Pharmacological actions of vita K
Correct bleeding due to hypoprothrombinemia in the following conditions: Essential for hepatic synthesis of activated
1. #Intake of vitamin K. coagulation factors II, VII, IX & X especially
3. #Absorption of vitamin K due to use of liquid paraffin, obstructive jaundice prothrombin
and malabsorption of fat.
2. #Synthesis of vitamin K by flora (uses of oral broad-spectrum antibiotics).
4. #Hepatic utilization of Vit K in newborn (immature liver) or liver diseases
5. Drug induced hypoprothrombinemia ! warfarin and salicylates over dose.
 Management of hyperlipoproteinemia #G3FR_34
[A] Diet regulation
1. #caloric intake. 3. # Cholesterol intake. 2. #Saturated fatty acids (animal fat). 4. Stop smoking. 5. " Unsaturated fatty acids (vegetable oils) 6. " Dietary fibers.
[B] Drug therapy
1- Hydroxy methyl glutaryl (HMG) 2- Fibrates 3- Niacin 4- Bile acid binding 5- Other Drugs
Co-A reductase inhibitor “Statins” resins
- Lovastatin. - Simvastatin - Fluvastatin - Clofibrate. - Fenofibrate Nicotinic acid Cholestyramine 1- Ezetimibe
- Atorvastatin - Pravastatin - Gemfibrozil Cholestipol
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MOA
HMG Co − A /⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯1 mevalonic acid→ cholesterol • Act as ligands for the nuclear transcription • (-) intracellular lipoprotein lipase • Resins bind with bile and small • Selectively inhibits intestinal absorption
receptor peroxisome proliferator activator of adipose tissues !#adipose tissue intestine ! forming insoluble of dietary and biliary cholesterol in small
• Statins inhibit HMG Co-A reductase in cholesterol receptors (PPAR-α) !regulate expression of lipolysis, circulating FFAs and liver complexes ! excreted in faces. intestine !#delivery of intestinal
synthesis. genes encoding for protein involved in lipoprotein FFAs • #Absorption of bile acids ! (+) cholesterol to liver !
• #cholesterol in liver cells !#synthesis of VLDL So, structure & function • #hepatic synthesis TG,# VLDL liver to increase conversion of - #hepatic cholesterol stores
statins decrease scrum level of LDL and VLDL. • (+) serum lipoprotein lipase enzyme (LPL) !" & LDL stored cholesterol to bile acids !# - "clearance of cholesterol from blood.
• Stimulates synthesis of LDL receptors and their up lipolysis of lipoprotein TG !"FFAs and increase hepatic cholesterol!"synthesis & • The effects are # LDL, # VLDL and
regulation that promote uptake of LDL from blood. oxidation of FFAs in hepatic & muscle. up regulation of LDL receptors. "HDL.
• (-) enzymes responsible for utilization of FFA in • "hepatic uptake of cholesterol • Not affect fat soluble vitamin
Liver for synthesis of triglycerides !#level of rich LDL from blood • Potentiate the effect of statins in LDL
VLDL and triglycerides. • #serum cholesterol and LDL. levels.
SE • Hepatotoxic (" transaminase enzymes) • Hepatotoxic (" transaminase enzymes) • Hepatotoxicity. 2- Estrogen hormone
• Myopathy (" serum creatinine kinase) • Myopathy (" serum creatinine kinase) • Hyperglycemia. # cholesterol
• GTT upset e.g. nausea. • GIT e.g. constipation & nausea • GIT: constipation and distension.
• " Incidence of cholesterol gall stones. • Cutaneous flush & pruritis due to • #Absorption of: 3- Fish oil
• Potentiate effect of warfarin anticoagulant. excessive production of PG - Fat-soluble vitamins, ADEK Omega 3 fatty acids !#triglycerides.
prevented by: aspirin or ibuprofen - Drugs e.g. digoxin, warfarin and 4- β-sitosterol
1/2 h before niacin chlorothiazides Plant sterol !#abs of cholesterol in diet
• #renal tubular secretion of uric 5- Neomycin
acid.! Hyperuricemia & gout Aminoglycoside ! prevent absorption of
DI • Myopathy with Rhabdomyolysis increases when statins • With statins ! sever liver and muscle damage bile acids and increase excretion in stool.
are used with ! Fibrates, Cyclosporine, Itraconazole 6- Probucol
and Erythromycin Antioxidant !# LDL
CI pregnancy, lactation and children • Pregnancy (cross placental barrier) & lactation. 7- Thyroxine
• Sever hepatic & renal impairment " cholesterol conversion to bile & " its
excretion in stool.
Combination therapy of anti-hyperlipidemic dugs
1- Statins + bile acid binding resin !#cholesterol. 2- Statins + nicotinic acid !#VLDL & TG. 3- Fibrate + bile acid binding resin !#TG, VLDL & LDL. 4- Don' t combine fibrate & statin ! severe liver & muscle damage