drugs acting on blood and blood forming organs
DESCRIPTION
For SY B Pharm students of Pune University.TRANSCRIPT
Pharmacology of drugs acting on blood and
blood forming organs
Dr Urmila M. Aswar,
Sinhgad Institute of Pharmacy, Narhe, Pune -41
Hemostasis: is a process which causesbleeding to stop, meaning to keep bloodwithin a damaged blood vessel (theopposite of hemostasis is hemorrhage)
Clotting disorders is a term used todescribe a group of conditions in whichthere is an increased tendency, oftenrepeated and over an extended period oftime, for excessive clotting.
Thrombophilia known as
hypercoagibility. It affects a large number
of people around the world. It affects
approximately 5% to 7% of the European
population.
Blood coagulation
Intrinsic pathway : all factors needed for
Blood coagulation are in plasma. Slow
process as lot many factors are needed to
be activated.
Extrinsic pathway: also needs tissue
factor-thromboplastin. Occurs with in
seconds.
Factors opposing coagulation
Antithrombin protein C,
Antithromboplastin
fibrinolysin
Thrombosis
Can be in artery or vein.
Symptoms depend on
Where it has formed
Area
Is it a emboli
There are different terms used to further define these thrombotic episodes, such as deep vein thrombosis (DVT) or peripheral vascular disease, when the clots are in the arterial system (usually in the extremities).
Triggering factors
Women are more sensitive
Pregnancy, oral contraceptives and post-
menopausal hormone replacement
therapy are all triggering events for DVT
in women with thrombophilia.
Factor V Leiden: hypercoagulation
factor V Leiden
Discovered in Leiden city of Neitherland
Factor V is responsible for activation of
factor X and XII which further stimulates
thrombin formation.
There is mutation in the gene responsible.
So that PK C couldn’t degrade factor V. so
it is over activity of factorV.
Anticoagulants
Used in vitro
Heparin
Ca complexing agents
Used in vivo
Heparin: LMW heparin
Oral anticoagulants: 1. Coumarin
derivatives
2. Indandione derivatives: Phenindione
Heparin
Isolated from liver
MW 10,000-20,000
Mucopolysacchride
chain
Contains negative
charge
Present in mast cells
Present in lung, liver
and intestine
Glycosaminoglycans
Actions
Activating antithrombin III
Binds to intrinsic clotting factors: Xa, IIa,
IXa, XIa, XIIa, XIIIa and blocks their
activity.
No effect onVIIa of extrinsic pathway.
It inhibits conversion prothrombin to
thrombin by Xa.
Also it inhibits conversion of fibrinogen to
fibrin, Inactivates IIa.
Low concentration interfere with intrinsic
pathway.
High affect both.
It inhibits platelet aggregation
It releases lipoprotein lipase from liver
and clears VLDL, chylomicrons and
triglycerides from plasma.
Kinetics
As it large inonized molecule, Not Absorbed orally
Does not cross BBB or placenta
T1/2: 1 hr
Units: 1U : the amt of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hr after addition of 1% CaCl2 solution
Heparin sod: 1 mg has 120-140U of activity
Dosage
Given IV 5,000-10,000U adults every 4-6
hrs
Infusion given (750-1000U) till bleeding
incidence happen.
Children: 50-100 U/kg
Adverse effects
Bleeding
Thrombocytopenia
Alopecia (transient)
Osteoporosis
Hypersensitivity reactions: urticaria, fever,
anaphyllaxis
Contradications
Bleeding disorders
Severe hypertension
Ocular and neurosurgery
Chronic alcoholics
Aspirin and other antiplatelet drugs
Low-molecular-weight heparins
(LMWHs) LMWHs, in contrast, consist of only short
chains of polysaccharide. LMWHs are
defined as heparin salts having an average
molecular weight of less than 8000 Da.
These are obtained by various methods of
fractionation or depolymerisation of
polymeric heparin.
LMWHs have a potency for factor Xaactivity and for anti-thrombin activity (ATIII).
More specific in action
Less effects on platelets
Less hemorrhagic complications.
Good p’kinetic profile
BA improves.
Longer T1/2
Dose is given in mg and not in unit
LAB MONITORING NOT NEEDED.
Uses
Pulmonary embolism
Deep vein thrombosis
Surgeries
Eg Nadoparin, Enoxaparin, Dalteparin,
Raviparin etc.
Fondaparinux
It is a synthetic pentasacchride. It is an antithrombin III mediated selective inhibition of factor Xa. Which further inhibits thrombin formation.
Administered s.c daily.
Dose: 2.5 mg
BA: 100%
T1/2: 17-21 hrs
Excreted unchanged in urine
Lesser antiplatlet action chances of thrombocytopenia is less.
Oral anticoagulants
Bishydroxycoumarin was made in 1941
Warfarin was used as anti-cogulant In vivo only.
They act by interfering with synthesis of vit Kdependent clotting factors.
They behave as competitive inhibitors of vit K.They interfere with regeneration of active form ofvitamin K, which is essential for carboxylation ofclotting factors-VII, IX, X.
Vitamin K is involved in the carboxylation ofcertain glutamate residues in proteins to formgamma-carboxyglutamate residues.
Caroboxylation enhances binding of clottingfactors to Ca2+ leading to coagulation.
Reduced Vitamin K Oxidised Vitamin K
Warfarin
NADNADH
Descarboxy factor: VII,IX,X Carboxylated factor: VII,IX,X
Synthesis of clotting factors diminishes within 2-4hrs of warferin administration the anticoagulanteffects develops gradually over next 1-3 days.
Therapeutic effect occurs when synthesis ofclotting factors is reduced by 40-50%.
Pharmacokinetics: Racemic warferin sodium:the most popular oral anticoagulant.
R+S, S is more potent, metabolized by oxidation.
Completely absorbed from stomach.
99% is plasma bound.
It crosses placenta and secreted in milk.
Bishydroxycoumarin (Dicoumarol)
Absorbed orally
Metabolism is dose dependent
T1/2 is prolonged at higher doses
Has poor GI tolerance
Available as 50 mg tab
Acenocoumarol
T1/2 of 8 hrs. produces an active
metabolite.
T1/2: 24 hrs.
Acts rapidly
Adverse effects
Bleeding
Epistaxis
Hematuria
Bleeding in GIT
Internal hemorrhage
Treatment:
Stop anticoagulant
Blood transfusion
Plasma replenishment
Vit K1 administration
Factors enhancing effect of oral
anticoagulants Malnutrition
Prolonged antibiotic use
Liver disease : low synthesis of CF
Newborns: low CF
Hyperthyroidism: Fast degradation of CF
Factors decreasing the effect of oral
anticogulants Pregnancy
Nephrotic syndrome: drug bound to
plasma protein is lost in urine.
Contraindications
Pregnancy: skeletal abnormalities, foetal
warfarin syndrome– hypoplasia of nose,
eye socket, hand bones and growth
retardation.
If given in later stage of pregnancy, it can
cause CNS defects, foetal death.
Drug interactions
Enhanced anticoagulant action
1. Braod spectrum antibiotics
2. Newer cephalosporins eg moxalactam, cefamandole, produces hypoprothrombinemia by the same mech. as warfarin.
3. Aspirin: inhibits platelet aggregation, also displaces warfarin from PBS.
4. Phenylbutazone: Decreases PB of warfarin
5. Long acting sulfonamides, indomethacin, phenytoin, probenicids: competitor for protein binding
6. Chloramphinicol, erthromycin, cimetidine, allopurinol, amidarone, metronidazole: inhibits warferin metabolism
7. Tolbutamide and phenytoin: inhibits warferin metabolism
8. Phenformin, anabolic steroids, quinidine, clofiberate, potentiate warferin action
9. Liq paraffin: reduces vit K absorption.
Reduced anticoagulant action
1. Barbiturates and other hypnotics (not
BZD), rifampin, grisofulvin induce
metabolism of oral anticoagulant
2. Oral contraceptives increases level of
clotting factors.
Uses
Deep vein thrombosis and pulmonary embolism: venous thrombi are fibrin thrombi- 3 month therapy
Post stroke required prophyllaxis.
Myocardial infarction: arterial thrombi are platelet thrombi. Not very beneficial. Aspirin+heparin followed by warfarin.
Rheumatic heart disease, auricular flutter: Warfarin/ low dose heparin/ low does aspirin
Cerebrovascular disease: little value
Preferred in ischaemic attacks due to
emboli.
Vascular surgery, prosthetic heart valves,
retinal vessel thrombosis: anticoagulants
are given along with antiplatelet drugs for
prevention of thromboembolism.
Fibrinolytics
These drugs are used to lyse the clot.
Curative
Fibrin is formed
Fibrinolytic system get activated
t-PA activates Plasminogen---Plasmin is
the serine protease which digest fibrin
Plasminogen is present in bound (fibrin)
and free form.
Fibrinolysis
Fibrinolytics
Strptokinase
Urokinase
Altelase
Streptokinase
Obtained from Streptococci C
Activates plasminogen
T1/2: 30-80 m
Antigenic
less expensive
Urokinase
Isolated from human urine
Prepared from human kidney cells
Activates plasminogen directly
T1/2: 10-15 m
Side effects: Less allergic
fever
Alteplase
Produced by recombinant DNA tech.
Activates plasminogen bound to fibrin.
T1/2: 4-8 m
Expensive
Uses
Acute MI
Therapy to be initiated 12 h of symptoms
Can be given IV
Heparin or aspirin is started thereoff
Deep vein thrombosis
Pulmonary embolism
Peripheral arterial occlusion
To be treated with in 72 hrs advised if throbectomy is not possible
Antiplatelet drugs
COX inhibitor: Aspirin
Aspirin is indicated as prophylaxis against
transient ischemic attacks, myocardial
infarction and thromboembolic disorders.
It is also used for the treatment of acute
coronary syndromes and in the
prevention of reoclusion in coronary
revascularization procedures.
Dose: 75 mg to 325 mg
Ticlopidine is the oldest thienopyridine
currently available. It is approved for
secondary prevention of thrombotic
strokes in patients intolerant of aspirin
and for prevention of stent thrombosis in
combination with aspirin.
Clopidogrel is approved for prevention
of atherosclerotic events following recent
myocardial infarction, stroke or
established peripheral arterial disease. It
has a better safety profile than ticlopidine.
Phosphodiesterase inhibitors
Dipyridamole acts as vasodilator and
antiplatelet agent. It blocks
phosphodiesterase in platelet leading to
increase in cAMP in platelet. Adenosine
decreases platelet aggregability.
It is used in combination with aspirin or
warfarin in the prophylaxis of
thromboembolic disorders.
GPIIb/IIIa inhibitors
Platelet membrane GPIIb-IIIa receptors
constitute the final common pathway of
platelet aggregation, the integrin
GPIIb/IIIa antagonists prevent cross-
linking of platelets.
Abciximab is a human-murine monoclonal
antibody directed against GPIIb/IIIa,
UESES
CAD: MI
Coronary bypass implant
Prosthetic heart valves
Venous thrombosis
Peripheral vascular disease