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Pharm > Homeostasis > Flashcards

Homeostasis Flashcards

1
Q

heparin

A

Commercial heparin obtained from hog intestinal mucosa or beef lung has an average molecular weight of approximately 15 kDa and is a linear polysaccharide composed of alternating residues of glucosamine and either glucuronic acid or iduronic acid. Heparin is strongly acidic. Additionally, the amino group of glucosamine is either acetylated or sulfated, whereas a variable degree of sulfation (up to 40%) occurs on the hydroxyl groups.

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2
Q

heparin moa

A

Heparin acts by binding to a plasma glycoprotein, ANTITHROMBIN III (AT-III) which serves as a major inhibitor of serine protease clotting enzymes. AT-III inhibits these enzymes by forming a stable 1:1 molar complex by association between an arginine-reactive site and the active center serine in the enzyme. Heparin binds to a lysine-rich site in AT-III, leading to a greatly enhanced rate of inhibition of thrombin, IIa, IXa, Xa, XIa, XIIa, XIIIa.(USUALLY THIS PROCESS IS SLOW)
——————-acts immediately

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3
Q

high dose heparin

A

inhibits thrombin, Xa, XIIa, and XIIIa. Chronic or intermittent administration of heparin can lead to a reduction in AT-III activity and increasing the risk of thrombosis.

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4
Q

low dose heparin

A

acts primarily by neutralizing factor Xa.

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5
Q

heparin uses

A
  • is the major antithrombotic drug for the treatment of deep vein thrombosis and pulmonary embolism.
  • Is used prophylactically to prevent postoperative venous thrombosis in patients undergoing elective surgery
  • In the acute phase of myocardial infarction
  • Used in dialysis machines to prevent thrombosis
  • D.O.C. for treating pregnant women with prosthetic heart valves or venous thromboembolism, because it does not cross the placenta. But,13-20 % of pregnant women can experience stillbirths and prematurity. Therefore use heparin cautiously especially the last trimester
  • Administered for short term use (days)
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6
Q

heparin pharmokinetics

A

Heparin must be given parenterally either in a deep subcutaneous site or intravenously

  • Heparin is often administered I.V. in a bolus dose to achieve immediate anticoagulation followed by lower doses or continuous infusion
  • never given I.M.—results in hematoma formation
  • binds to many different proteins that neutralize it’s activity
  • metabolized by reticuloendothelial system and liver
  • inactive metabolites and heparin are excreted in urine, so in patients with either liver cirrhosis or kidney failure will increase the ½ life
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7
Q

heparin adverse

A

BLEEDING COMPLICATIONS: Hemorrhage-careful monitoring of bleeding time is required to minimize this problem

HYPERSENSITIVITY REACTIONS: chills, fever, urticaria, and or anaphylactic shock— heparin is obtained from animal sources and maybe antigenic
THROMBOCYTOPENIA— (H.I.T) a decrease in the number of circulating platelets may occur after 8 days of therapy. Some patients develop antiplatelet antibodies

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8
Q

heparin contraindications

A

In those patients that have bleeding disorders, alcoholics, hypersensitive, surgery of the brain, eye, or spinal cord.

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9
Q

ENOXAPRIN (LOVENOX)-

A

low-molecular-weight-fractions of Heparin (LMWH)—produce longer anticoagulation than unfractionated heparin
-has the same adverse reaction profile as heparin

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10
Q

WARFARIN (COUMADIN)

A
  • Initially used as a rodenticide

- Known as the “oral anticoagulant” but can be given I.V.

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11
Q

warfarin moa

A

-Several of the protein factors—II, VII, IX, and X that are involved in clotting reactions depend upon vitamin K as a cofactor in their synthesis by the liver.
–these factors undergo vitamin K dependent posttranslational modification—a number of their glutamic acid residues are carboxylated to form g-carboxyglutamic acid residues
–the vitamin K-dependent carboxylases fixes CO2 to form new COOH group on glutamic acid, and reduced vitamin K is converted to an epoxide.
Vitamin K is regenerated from the epoxide by vitamin K epoxide reductase It is this enzyme that is inhibited by WARFARIN
-g-carboxyglutamic residues bind calcium ion and are essential for interaction with cell membranes.—-the net result is inactive clotting factors
– the effects of warfarin are not observed until 8-12 hours after administration,

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12
Q

warfarin pharmokinetics

A
  • rapid and complete absorption following oral administration
  • warfarin is 99% bound to plasma albumin-prevents its diffusion into cerebrospinal fluid, urine, and breast milk
  • warfarin does cross the placental barrier-teratogenic and can cause abortions
  • products of warfarin metabolism are inactive and are excreted in the urine
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13
Q

warfarin adverse

A
  • BLEEDING DISORDERS-hemorrhage-frequently monitor and adjust the anticoagulant effect.
  • DISEASE STATES-hepatic disease, vitamin K deficiency augment the response to warfarin
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14
Q

RIVARPXABAN

A

An oral factor Xa inhibitor
Clinical trial data have shown that it allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring.[ Clinical trial data have shown that it allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring.

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15
Q

DIRECT THROMBIN INHIBITORS

A

Thrombocytopenia (a condition in which circulating blood contains an abnormally small number of platelets)
One factor causing this condition in hospitals is thru the use of heparin
Two types of heparin-induced thrombocytopenia (HIT)
(A) HIT I- is a mild decrease of platelets due to nonimmunologic mechanisms and is not serious (usually occurs 2 to 4 days)
(B) HIT II- can become life threatening (a.k.a. WHITE CLOT SYNDROME)
Occurs 6-12 days
Antibodies to FACTOR 4

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16
Q

Direct thrombin inhibitors

A

ARGATROBAN

DABIGATRAN

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17
Q

ARGATROBAN

A

M.O.A.- Direct Thrombin Inhibitor (injected)

  • used in patients that develop HIT
  • Can be used in kidney failure
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18
Q

DABIGATRAN

A

Oral Direct Thrombin Inhibitor
(A) M.O.A.- reversible inhibitor at the active site of thrombin
(B) Used for venous thromboembolism & atrial fibulation
(C) Being investigated for causing M.I.’s

19
Q

aspirin moa

A

platelet aggregation inhibitor
blocks thromboxane A2 synthesis from arachidonic acid in platelets by irreversible acetylation and inhibition of cyclooxygenase.
-the suppression of platelet aggregation last for the life of the platelet (7-10 days)

20
Q

aspirinuses

A

the prophylactic treatment of transient cerebral ischemia
- to reduce the incidence of recurrent myocardial infarction
- to decrease mortality in postmyocardial infarction patients.
Loading dose of 200-300mg then a daily dose of 75-100mg
Bleeding time is prolonged- an increased incidence of hemorrhagic stroke as well as gastrointestinal bleeding

21
Q

TICLOPIDINE

A

moa- Inhibits ADP pathway involved in the binding of platelets to fibrinogen and to each other.

  • has been shown to decrease the incidence of thrombotic stroke
  • orally active—can cause prolonged bleeding
  • neutropenia is the most serious side-effect, therefore reserved for patients who cannot tolerate aspirin.
22
Q

PRASUGREL

A

(A)M.OA.- Inhibits ADP pathway involved in the binding of platelets to fibrinogen and to each other.
(B)Considered to be a prodrug
(C)It’s onset of action is more rapid than that ticlopidine or clopidogrel and produces greater and more predictable inhibition of ADP-induced platelet aggregation.

23
Q

CLOPIDOGREL

A

(A) M.O.A- selectively inhibits the binding of ADP to its platelet receptor inhibiting platelet aggregation.
(B) USES: same as aspirin, prevention of ischemic stroke or myocardial infarction.
(C) Has not been shown statically more effective than aspirin. But it is synergistic with aspirin

24
Q

TICAGRELOR

A

(A) M.O.A.- Inhibits ADP pathway involved in the binding of platelets to fibrinogen and to each other.
(B) Ticagrelor produced a greater reduction in cardiovascular death, myocardial infarction and stroke at 1 year than clopidogrel

25
Q

CILOSTAZOL

A

(A) M.O.A – Inhibits phosphodiesterase III, increasing levels of cAMP, leading to inhibition of platelet aggregation and vasodilation
(B) USE- to treat intermittent claudication-given orally
(C) Caution: coadministration of aspirin showed a 23-35% inhibition of ADP-induced platelet aggregation when compared to aspirin alone.
(D) May increase heart rate in particular may cause ventricular tachycardia

26
Q

DIPYRIDAMOLE

A

M.O.A-In platelets it inhibits cyclic nucleotide phosphodiesterase-increases intracellular levels of cAMP

  • usually given in combination with aspirin, but make only a marginal contribution to the effect of aspirin.
  • however warfarin with dipyridamole is effective in inhibiting embolization from prosthetic heart valves
27
Q

GP IIb/IIIa MODIFERS

A

Platelet activation agents all promote the conformational change necessary for the Glycoprotein Protein IIb/IIIa (GP IIb/IIIa) to bind to ligands, particularly fibrinogen. In the aggregation step fibrinogen simultaneously binds to GP IIb/IIIa receptors on two separate platelets, resulting in platelet crosslinking and aggregation.

28
Q

ABCIXIMAB (RePRO)

A

(A) M.O.A- abciximab is a monoclonal antibody directed against the GP IIb/IIIa complex. By binding to GP IIb/IIIa blocks the binding of fibrinogen.
(B) Abciximab is given I.V. as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications
(C) platelet function gradually returns in about 24-48 hours.

29
Q

TIROFIBAN

A

(A) M.O.A.- mimic the arginine-glycine-aspartic acid sequence of fibrinogen and acts as an antagonist at the GP IIb/IIIa receptor
(B) has the same indications as abciximab

30
Q

EPTIFIBATIDE

A

(A) an antagonist at the GP IIb/IIIa receptor
(B) Given I.V.
(C) Duration of action is short and platelet aggregation is restored within 6-12 hours after cessation
(D) Generally administered in conjunction with aspirin and heparin.

31
Q

fibrinolytic system

A

The fibrinolytic system is involved in the restricting clot propagation in the blood and in the removal of fibrin as wounds heal.
Treatment of patients with thrombolytic drugs that activate the fibrinolytic system is not a substitute for anticoagulants. On the other hand, anticoagulants and anti-platelet drugs are administered prophylactically to prevent thrombus formation and propagation, while the purpose of thrombolytic therapy is to rapidly lyse already formed clots. The thrombolytic drugs produce more profound alterations in the blood than are produced with anticoagulants and antiplatelet drugs

32
Q

Fibrinolysis

A

is initiated by the activation of the proenzyme plasminogen to plasmin, a protease enzyme not normally present in the blood. Plasmin catalyzes the degradation of fibrin. The conversion of plasminogen to plasmin is initiated normally by the plasminogen activators

(1) tissue-type plasminogen activator (t-PA)
(2) single chain urokinase-type plasminogen activator (su-PA)

t-PA and su-PA are serine protease enzymes synthesized by the endothelium and released into the circulation. The endothelium also releases plasminogen activator inhibitor-1 (PAI-1), which complexes with and inactivates t-PA in the plasma.

33
Q

t-PA and su-PA

A

t-PA and su-PA bind with high affinity to fibrin on the clot surface. Circulating plasminogen binds to the plasminogen activator-fibrin to form a ternary complex consisting of fibrin, activator, and plasminogen.
So that the specificity of t-PA and scu-PA binding to fibrin normally localizes plasmin protease activity to thrombi.

Circulating plasmin is rapidly neutralized by a2 –antiplasmin, a physiological serine protease inhibitor that forms an inert complex with plasmin. In contrast, fibrin-bound plasmin is resistant to inactivation a2 –antiplasmin. Under normal circumstances plasma t-PA is inactive because it is inhibited by PAI-1, while t-PA bound to fibrin is unaffected by PAI-1.
In addition, plasma t-PA has a very rapid turnover in the blood (t1/2= 5-8 minutes). For these reasons , fibrinolysis is normally restricted to the thrombus.

34
Q

Activation of the fibrinolytic system

A

with thrombolytic drugs can disturb the balance of these regulatory mechanisms and elevate circulating plasmin activity. Plasmin has low substrate specificity and can degrade fibrinogen (fibrinogenolysis), plasminogen, a2 –antiplasmin, and factors V and VIII. The systemic activation of the fibrinolytic system with thrombolytic drugs causes consumption of the coagulation factors, a lytic state, and bleeding.

35
Q

THROMBOLYTIC DRUGS uses

A

(1) used for the treatment of deep-vein thrombosis and serious pulmonary embolism
(2) treat myocardial infarction
(3) peripheral arterial thrombosis and emboli
(4) un-clotting catheters and shunts

36
Q

STREPTOKINASE moa

A

Is an extracellular protein purified from culture broths of Group C beta-hemolytic streptococci.
M.O.A.- has no enzyme activity, instead it forms an active 1:1 complex with plasminogen, which then converts uncomplexed plasminogen to the active enzyme plasmin. In addition to the hydrolysis of the fibrin plugs, the complex also catalyzes the degradation of fibrinogen as well as clotting factors V and VII.

37
Q

STREPTOKINASE pharmokinetics

A
  • is administered within 4 hours of a myocardial infarction and is infused for 1 hour.
  • half-life is less than a half-hour
38
Q

STREPTOKINASE ADVERSE EFFECTS

A

-Activation of circulating plasminogen leads to elevated levels of plasmin, which may precipitate bleeding by dissolving hemostatic plugs

-HYPERSENSITIVITY- streptokinase is a foreign protein and is antigenic. Rashes, fever, and rarely anaphylaxis occurs.
- if you have had a strep infection, then you are likely to have antibodies for this drug. Therefore sufficient quantities of streptokinase must be administered to overwhelm the antibodies

39
Q

UROKINASE

A

M.O.A- Is an enzyme capable of directly degrading both fibrin and fibrinogen.

  • originally isolated from human urine, but now obtained from cultures of human fetal renal cells
  • used in patients who are sensitive to streptokinase, it is not a foreign body and not antigenic
  • bleeding is the most important side-effect
40
Q

ANISTREPLASE

A

(acetylated streptokinase-plasminogen activator complex, ASPAC)

  • consists of streptokinase in a noncovalent 1:1 complex with plasminogen.
  • ANISTEPLASE is catalytically inert due to the acylation of the catalytic site of plasminogen-so it is inactive till it binds to fibrin,
  • it has a long catalytic half-life (90 minutes) and the time required de-acylation lengthens its thrombolytic effect after IV injection
  • it is antigenic
41
Q

ALTEPLASE (tissue-type plasminogen activator) (tPA)

A

M.O.A.-ALTEPLASE has a low affinity for free plasminogen, but it rapidly activates plasminogen bound to fibrin in a thrombus or hemostatic plug. Therefore, alteplase is said to be “fibrin selective” and at low doses, has the advantage of lysing only fibrin, without unwanted degradation of other proteins, notably fibrinogen.

  • this contrasts with urokinase and streptokinase, which act on free plasminogen and induce a thrombolytic state
  • ALTEPLASE seems to be superior to urokinase and streptokinase in dissolving older clots
  • has a short half-life of about 5 minutes
  • bleeding complications
42
Q

DRUGS TO TREAT BLEEDING

A 
Bleeding problems may have their origin in naturally occurring pathological conditions such as hemophilia, or as a result of fibrinolytic states that may arise after surgery, and the use of anticoagulants
AMINOCAPROIC ACID (Amicar)
M.O.A.- inhibits plasminogen activation
PROTAMINE SULFATE
VITAMIN K (PHYTONADIONE)
43
Q

PROTAMINE SULFATE

A

Antagonizes the anticoagulant affects of heparin
-it is derived from fish sperm and testes and is high in arginine content (highly basic)
M.O.A- the positively charged protein interacts with the negatively charged heparin to form a stable complex without anticoagulant activity.
-can interfere with coagulation when given in the absence of heparin (interacts with platelets and fibrinogen)

44
Q

VITAMIN K (PHYTONADIONE)

A
  • interferes with the anticoagulant activity of warfarin

- response is slow, usually requiring 24 hours

Pharm (21 decks)

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