Transcript Drugs used for treatment of coagulate disorders

Drugs used for treatment of
coagulate disorders
Clinical Thrombosis
> 2.5 million cases of deep venous
thrombosis (DVT) per year
 > 600,000 cases of pulmonary
embolism (PE) per year
 > 50,000 deaths per year from PE
 > 11,000 post surgical PE deaths per
year

ANTITHROMBOTIC THERAPY
1) Antiplatelet therapy
2) Anticoagulant therapy
3) Thrombolytic therapy
INHIBITORS OF PLATELET AGGREGATION
Anti Platelet Drugs
Drug
Aspirin
Mechanism
Permanently
inhibits COX-1
and COX-2
Uses
NSAIDs
Reversibly
inhibits COX-1
Dipyridamole
Inhibits PDE;
TIAs
increases cAMP
Ticlopidine
Clopidogrel
Inhibits ADP
PlatAg; active
metabolite
CAD
Stroke-TIAs
Limited
TIAs; Stroke
CAD; PVD
Platelets inhibitors - ASA
Kardiomagnil
Daily dose - 80-300 mg
ANTIPLATELET THERAPY
Aspirin Indications
1) Stroke, TIA (transient ischemic
attacks)
2) MI, recurrent MI
3) Unstable angina
4) CABG potency (coronary
artery bypass graft )
TICLOPIDINE
1) Interferes with platelet-fibrinogen binding
2) Exerts its action for the life of the platelet
3) May prolong bleeding time
4) Useful for coronary artery stents and CVA
(cerebrovascular accident )
5) Methylprednisolone may reverse its effect
6) Associated with TTP (thrombocytopenic
purpura), neutropenia, and diarrhea
CLOPIDOGREL
1) Interferes with GP IIb/IIIa
(Glycoprotein IIb/ IIIa ) binding site
2) Exerts its action for the life of the
platelet
3) May prolong bleeding time
4) Indicated for prevention of MI, CVA, and
vascular death
5) Fewer side effects than ticlopidine
6) Dose: 75 mg daily
Abciximab (ReoPro)
1)
2)
3)
4)
5)
Human-mouse monoclonal antibodies
Binds to GP IIb/IIIa receptor on platelets
Half-life 10 min.
May block receptor for 10 days
Indicated for prevention of closure of
coronary vessels after angioplasty
6) May cause thrombocytopenia
7) Used with heparin and ASA
Ant platelet
therapy
Recombinant Human
Activated Protein C
Drotrecogin alfa (activated)- Xigris
 Indicated for Severe Sepsis in
Adults with Acute Organ
Dysfunction with High Risk of
Death
 Reduction in Death as Primary End
Point
 Antithrombotic, Antiinfammatory,
Profibrinolytic Properties
 Serious Bleeding is Major Side

Antithrombin III Inhibits the Following
Serine Proteases

Coagulation

Fibrinolysis

Factor XIIa
Factor XIa
Factor IXa
Factor Xa
Thrombin

Plasmin
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Inhibitory activity against all these enzymes is substantially accelerated by heparin
HEPARIN (Description)
1)
2)
3)
4)
5)
6)
7)
8)
Discovered in 1916 by McLean; isolated from liver,
thus the name heparin
Anionic glycosaminoglycan available as calcium or
sodium salt, negative charge
Molecular weight 15,000 D (avg.) (3000-30000 D)
Prepared from porcine intestinal mucosa and
bovine lung
Does not cross placenta
Little interaction with other medications
IV or SC administration only
Reversible with protamine sulfate (1 mg/200 U
heparin)
Heparin
About 1/3 of dose binds to AT III
 To form the AT III:Heparin:Clotting
Factor Complex- requires at least 18
saccarides except
 Unique high affinity pentasaccaride
heparin sequences catalyze inhibition
of Xa by AT

HEPARIN (Action)
Binds to and potentiates
antithrombin III
2) Heparin-antithrombin III complex
inactivates thrombin (factor IIa) and
factor Xa (Stuart-Prover)
3) Secondary effect against platelet
function
1)
Monitoring of Anticoagulant
Therapy with Heparin
Heparin
s.q. – no monitoring required
i.v. - APTT
Activated Partial Thromboplastin Time
i. v. - no less than 4 times daily or more
frequent if PTT varies
therapeutic goal – 2-2.5 times normal
control value (-30 sec)
HEPARIN (Indications)
Full Dose: 5000 U or 80 U/kg IV bolus, followed by 1200-1600
U/hr adjusted to therapeutic range
1) Acute deep venous thrombosis
2) Pulmonary emboli
3) Unstable angina and myocardial infarction
Low Dose: 5000 U sq q12 h
1) Postoperative prophylaxis of any major abdominal,
thoracic, gynecologic, or orthopedic procedure
2) Immobilized medical patients >40 yrs. with CHF, CVA,
malignant disease
3) Prophylaxis for underlying hypercoagulable state
Other Dose:
1) Extracorporeal bypass
2) Hemodialysis
3) After thrombolytic therapy
Heparin
 Pregnancy-
YES
HEPARIN (Contraindications)
1)
2)
3)
4)
5)
6)
Thrombocytopenia
Aspirin or alcohol use
Hepatic or renal disease
Other platelet dysfunction
GI bleeding
Tumors
HEPARIN (Side Effects)
1) Major side effect is bleeding
2) Osteoporosis with prolonged
use
3) Thrombocytopenia
HEPARIN-INDUCED THROMBOCYTOPENIA
1) Occurs in 2-5% of patients receiving standard
heparin by immune mechanism
2) May occur with minute doses, including heparin
flushes
3) More common with bovine than porcine heparin
4) Asymptomatic thrombocytopenia can occur in 3050% of pts who develop HIT antibodies
5) ~20-50% of thrombocytopenic patients develop
arterial or venous thrombosis that may be life
threatening
HEPARIN-INDUCED THROMBOCYTOPENIA
Usually appears 3-15 days after
starting heparin, peak incidence
day 8
2) Diagnosis is largely clinical despite
availability of several tests used to
attempt confirmation
1)
HEPARIN-INDUCED
THROMBOCYTOPENIA
Alternative Anticoagulants
1)
2)
Lepirudin
Argatroban
LEPIRUDIN
1) Recombinant form of hirudin
2) Highly specific direct thrombin
inhibitor
3) Short half-life 1-2 hours
4) Monitored by APTT
5) Crosses placenta in rats, would not
use in pregnancy at present
6) No antidote
LOW MOLECULAR WEIGHT
HEPARIN
1) Molecular weight 3,000- 7,000 D
2) Inhibits factor Xa rather than thrombin
3) Factor Xa assay used for monitoring
4) Administered subcutaneously 2 times/d
5) Probably less antigenic than standard
heparin
6) Recommended for prophylaxis and
treatment
LOW MOLECULAR WEIGHT
HEPARIN
1) PT, APTT not usually prolonged
2) May be monitored with anti-factor Xa
assay
LOW MOLECULAR WEIGHT
HEPARINS
Indications for and Contraindications to
Parenteral Anticoagulant Agents
Anticoagulant
Agent
Unfractionated
heparin
Enoxaparin
(Lovenox)
Dalteparin
(Fragmin)
Tinzaparin
(Innohep)
Class
Approved & Appropriate
Indications
Antithrombi Treatment of venous
n III
thromboembolism or
inhibitor
unstable angina; used
when rapid reversal is
important
Prophylaxis in moderateLowrisk or high-risk patients,
moleculartreatment of venous
weight
thromboembolism or
heparin
unstable angina
LowProphylaxis in moderatemolecularrisk or high-risk patients,
weight
treatment of venous
heparin
thromboembolism or
unstable angina
LowProphylaxis in moderatemolecularrisk or high-risk patients,
weight
treatment of venous
heparin
Contraindication
?Prophylactic
treatment
Regional anesthesia
Pregnancy
Prosthetic Heart
Valves
Regional anesthesia
Regional anesthesia
Heparin-Antibiotic Interactions
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The cephalosporins- cefamandole, cefotetan,
and cefoperazone, contain an Nmethylthiotetrazole (NMTT) side chain. This
NMTT group can:
- Dissociate from the parent antibiotic in solution
or in vivo and competitively inhibit vitamin K
action, leading to prolongation of the
prothrombin time and bleeding.
- This side chain is also associated with a
disulfiram-like reaction to alcohol.
- Clinical bleeding has been less frequently
reported with Cefotetan than with
cefoperazone or cefamandole.
ANTICOAGULANTS
OF INDIRECT ACTION
COUMARIN (Description)
1) Isolated by Link in 1939 after previous
observation that cattle developed
bleeding
disorder after ingestion of
spoiled clover
2) Is 4-hydroxycoumarin compound, similar
in structure to vitamin K
3) Administered p.o., rapid GI absorption
4) Crosses placenta easily (complications!)
5) Interacts with a variety of drugs
COUMARIN (Actions)
1) Blocks the carboxylation of the
vitamin K dependent clotting
proteins, factors II, VII, IX, and X,
maintaining them in their inactive
forms
2) Blocks the anticoagulant proteins
C and S
3) Onset – 18-48 hours
PLASMA HALF-LIVES OF VITAMIN K
DEPENDENT CLOTTING FACTORS
Factor II
Factor VII
Factor IX
Factor X
Protein C
Protein S
Hours
60
6
24
30
6
42
COUMARIN
Laboratory
1) Prolongs the PT and APTT
2) PT and Prothrombin index -used
for monitoring
INTERNATIONAL NORMALIZED RATIO
(INR)
INR
=
PATIENT PT
CONTROL PT
COUMARIN Side Effects
1) Hemorrhage
2) Fetal abnormalities
3) Skin necrosis with deficiencies of
proteins C or S usually on 3rd to 8th
day of therapy
COUMARIN-INDUCED SKIN
NECROSIS
1) Usually occurs on days 3-8 after
initiation of Coumarin
2) More common in females (75%)
3) Most common on the breast,
buttocks, or extremities, occ. on
penis in males
4) Not predictable by history or
protein C level
COUMARIN Interactions
POTENTIATORS:
Phenylbutazone
Cimetidine
Omeprazole
Amiodarone
Anabolic steroids
ANTAGONISTS:
Barbiturates
Rifampin
Penicillins
Antacids
Warfarin
 Pregnancy-
NO
Contraindication towards administration of
anticoagulants of indirect action
Hemorrhagic diatheses
 Ulcer of stomach and duodenum
 Ulcerative colitis
 Pregnancy
 Malignant formations
 Disturbance of functions of kidneys,
liver

Mechanism of action of thrombolytic
agents

Blood plasma

Profibrinolysin
(plasminogen)
Profibrinolysin
(plasminogen)
+ Streptokinase+profibrinolysin
+
Urokinase
Fibrinolysin
(plasmin)
Decomposition
products
Thrombus
Fibrinogen
+
+
Fibrin
Activators
+ Tissue activator of
profibrinolysin
Fibrinolysin
(plasmin)
Fibrin
Decomposition
products
Pharmacodynamics of fibrinolytic drugs
After introduction into organism they
cause lyses of fresh (24-72 hours)
thrombi in arteries, veins, cavities
 The most effective during the first 2-3
hours after initiation of thrombosis

Administration of fibrinolytics
Thrombosis, thromboembolia of:
 - lungs
 - brain
 - eye retina
Myocardium infarction
Thromboses of profound veins
Heparin often used after initial thrombolytic therapy
Side effects of fibrinolytics

Hemorrhages (prothrombine index
(decreasing no less than 30-40 %), clotting
time (increasing no more than 2 times),
fibrinogen content (not <1 h\l) should be
under the constant control)
 Allergic reactions (face hyperemia,
abdominal pain, pain behind the sternum,
chill, raised body temperature – these are
reactions on foreign protein)

Contraindications: hemorrhagic diatheses,
hemorrhages. Open wounds, ulcer disease.
Nephritis, acute form of tbc, x-ray disease.
Drugs influencing on
leuko- and erythropoesis
Combined drugs
Actiferrin
Iron sulfate, D,L- serin
Iron sulfate, D,L- serin, glucose, fructose
Caps., 11385 g
syrup 5 ml – 171 mg
34,5 mg
34 mg
Sorbifer-durules
Iron sulfate, ascorbatic acid
Tab., 320 mg
100 mg
Ferrplect
Iron sulfate, ascorbatic acid
Tab., 50 mg
10 mg
Ferroplex
Iron sulfate, ascorbatic acid
Tab., 50 mg
10 mg
Fefol
Iron sulfate, folic acid
Tab., 150 mg
47 mg
Ferro-folgamma
Iron sulfate, folic acid, vit. В12
Caps., 100 mg
20 mg
Tardiferron-retard
Iron sulfate, ascorbatic acid,
mucoprotease
Dragee, 256,3 mg
80 mg
Gyno-tardiferron
Iron sulfate, ascorbatic acid,
mucoprotease, folic acid
Dragee, 256, 3mg
80 mg
Fenulse
Iron sulfate, ascorbatic acid, nicotinamid,
vitamins of B group
Capsules
45 mg
Irovit
Iron sulfate, ascorbatic acid, folic acid,
ciancobalamine, lysine
Caps., 300 mg
100 mg
Ferrostab
Iron fumarate, folic acid
Tab., 154 mg
33 %
Folfetab
Iron fumarate, folic acid
Tab., 200 ,mg
33 %
Globiron
Iron fumarate, folic acid, vitt. В6, В12.
Caps.
Macrofer
Iron gluconate, folic acid
Tab., 625 mg
12 %
Iron SULFATE (gradumet
substance)
Iron SULFATE+ascorbatic acid+mucoprotease
Iron SULFATE+ascorbatic acid+mucoprotease

Iron SULFATE+ascorbatic acid
Iron SULFATE+ascorbatic acid
Multofer
(Fe3+ -hydroxide polymaltose complex)
Iron asparginate (Fe3+)

Iron fumarate
Criteria of iron drugs therapy effectiveness
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Increasing of reticulocytes quantity on 5-7th day after
administration
Normalization of blood iron-binding function indexes (not only
indexes of peripheral blood)
If the latter get normalized during 1-2 months of therapy, than
saturation of depot get normalized on 3rd month. On this stage
dose of the drugs must be decreased to 60-80 mg of elementary
Fе per 2 hours.
If the reason of blood loss has been eliminated administration of
the drugs is determined by iron metabolism indexes.
If the reason of iron loss is not eliminated supportive therapy is
carried on according to the following: 20-40 mg of elementary Fe
per day during a week and after 3-4 weeks of brake and so on.
Complications of therapy with peroral
iron drgus
Activation of free-radical processes
 Nausea, vomiting, diarrhea (irritation

of mucous membranes)
Constipations (FeS production)
 Melena
 Black coloring of teeth
 Appearance of metallic taste in the
mouth

Indications towards administration of
parenteral forms of iron
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Condition after gastrectomy
Condition after massive resection of
small intestine
Heavy enteritis
Parenteral nutrition
Haemodyalysis
Psychogenic anorexia
Drugs for parenteral introduction
Ferbitol
Chelate substances
Amp., 1 ml i.m.
50 mg
Ferlecyt
Chelate substances
Sodium gluconate complex
Amp., 1 ml i.m.
Amp., 5 ml i.v.
50 mg
100 mg
Fercoven
Polynuclear hydroxyl complexes of
iron, saccharate of iron, gluconate of
cobalt
Amp., 1 ml i.v.
20 mg
Polynuclear hydroxyl complexes of
iron, sorbitol, citric acid
Amp., 2 ml i.m.
100 mg
Polynuclear hydroxyl complexes of
iron. Polymaltose complex
Amp., 2 ml i.m.
Amp., 5 ml i.v.
100 mg
100 mg
Жектофер
Ferrum-lek
Maltofer
-\\-
Amp., 2 ml i.m.
100 mg
Venofer
-\\-
Amp., 5 ml i.v.
100 mg
Polynuclear hydroxyl complexes of iron
(polyisomaltosate of iron)
Calculation of dose of drugs for parenteral
introduction
А=Кх(100-6Hb)х0,0066,
where А – quantity of ampoules of drug with
contents of 100 mg of Fe (per treatment coarse);
К – patient’s body weight (kg);
Hb – contents of hemoglobin in g %
А=(Кх2,5)х [16,5-(1,3Hb)],
where А – quantity of iron mg per coarse;
К – body weight (kg);
Hb – contents of hemoglobin (g\100 ml)
More than 100 mg of elementary iron per day should not be
introduced
Complications which develop during
parenteral iron introduction

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Phlebitis, after-injection abscesses, pain in the place of
introduction;
Allergic reactions;
Hyperemia of face, neck, feeling of pressure behind sternum,
pain in lumbal area, sternocardia (can be relieved with
analgesics+0,5 ml of atropine sulfate);
Arterial hypotonia;
Darkening of skin in place of introduction.

Contraindications: hemochromatosis, liver diseases, coronary
insufficiency, essential hypertension of ІІ – ІІІ stages, acute
nephritis.

In case of acute poisoning with iron drugs deferroxamine and
EDTA are introduced
Hyperchrome anemia

а) megaloblast
Erythroblast
Hyperchrome megaloblast
Megalocyte
Cyanocobalamine, oxycobalamine (are transformed into
cobamamid) and folic acid are introduced.

б) macrocytar
Erythroblast
Macrocyte
Folic acid is used
Hyperchrome macronormoblast
Erythremia (polycytemia)

Anti-blastoma drug imifod and
radioactive isotopes of phsophorus (32Р)
are used
Other drugs used for hypochrome anemia


Cobalt drus (coamid)
Human recombinant erythropoetin (eportin
alfa, epogen, eprex)
Leucopoesis stimulants
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

Mechanism of action is based on their participation in piramidine bases
synthesis, which are necessary for synthesis of nucleonic acids
Drugs:
- methyluracyl (doesn’t have irritative action, ways of introduction;
perorally, rectally locally);
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- pentoxyl (possesses irritative action, administered
perorally after a meal, with milk);
- sodium nucleonate (introduced perorally and i.m.,
possesses irritative activity).
Nowadays also stimulants of new type were synthesized – activators of
colony-producing factor of leucopoesis:
- molgramostim (granulocyte-macrophagal colony-stimulating factor
and
- filgrastim (granulocytar colony-producing factori)
Folic acid

Folic acid

Drugs which depress leucopoesis
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Are administered in case of leucosis and
lymphogranulomatosis
Antiblastome drugs refer to this group:
- methotrexate
- merkaptopurine
- chlorbutin
- mielosan
- vinblastin
- vinkristin