Drugs Opposing Homeostasis

By Dr Barakat Shahin

1 Drugs Opposing Homeostasis By Dr Barakat Shahin DEFINITION The normal physiological process, to arrest a hemorrhage is called homeostasis. COMPONENTS It has three major components. 1. Vasoconstriction, 2. Platelet plugging, 3.Coagulation in the local region. DRUGS Antithrombotic or Antiplatelet They effect by opposing platelets activation, i.e. Aspirin (in low dose), Sulfinpyrazone and Dipyridamole. Anticoagulants They effect by opposing procoagulant, i.e. Heparin, Warfarin and the other coumarin anticoagulants.

Thrombolytics They effect by promoting fibrinolysis, i.e. Streptokinase, Urokinase, tissue plasminogen activator (tPA).

2 Drugs Opposing Homeostasis By Dr Barakat Shahin Antithrombotics or antiplatelets

Since aggregation of platelets serves as a focus for initiation of blood clotting, it is thought that inhibitors of platelet aggregation may be value in the Rx of thrombotic diseases with antithrombotics

3 Drugs Opposing Homeostasis By Dr Barakat Shahin Individual drugs Aspirin: There are two sets of chemicals acting on the platelets: i. TxA 2 cause platelet activation, i.e. leading to platelet adherence, aggregation, secretion and vasospasm. ii. The other set, i.e. prostacycline, (PGI2) leading to platelet inactivation and vasodilatation.

TxA2 is produced by the platelet through cyclooxygenase pathway but PGI2 from vascular endothelium although through cyclooxygenase pathway. Aspirin in low doses inhibits the platelet cyclooxygenase pathway but not the endothelium cyclooxygenase pathway

(in other words TxA2 synthetase but not the PGI2 synthetase) so that Aspirin in low doses opposes homeostasis by suppressing TxA2 but, PGI2 is not suppressed.

The great use of aspirin as antihomeostatic agent is as prophylaxis where there is increased risk of blood clotting, i.e: i. Angina pectoris ii. Early in MI iii. Coronary artery bypass graft iv. Atrial fibrillation particularly in the elderly where use of warfarin can be risky. Further details of aspirin see in CNS Dipyridamole It inhibits the phosphodiesterase enzyme. Inhibition of phosphodiesterase causes accumulation of cAMP. Accumulation of cAMP within the platelet causes inhibition of release of ADP, so no platelet aggregation occurs. However, as an antiplatelet agent, it is weak and usually given with aspirin

4 Drugs Opposing Homeostasis By Dr Barakat Shahin 5 Drugs Opposing Homeostasis By Dr Barakat Shahin 6 Drugs Opposing Homeostasis By Dr Barakat Shahin Role of vitamin K in coagulation: The role played by vitamin K in the synthesis of prothrombin and factors II, VII, IX and X has not been fully elucidated. There are three main hypothesis:

First one is that the genes controlling the synthesis of protein clotting factors operate in conjunction with a gene that produces a repressor substance. The inhibitory effect of the repressor substance is prevented by vitamin K. Therefore, synthesis proceeds. In the absence of vitamin K, synthesis is suppressed.

The second hypothesis depends on the fact that the vitamin K, dependent clotting factors are glycoproteins and invokes the following scheme in the attachment of the carbohydrate moiety to the peptide chain

The third hypothesis proposes that vitamin K is a necessary cofactor in the final stage of the synthesis of prothrombin and factors II, VII, IX, with X. This final stage is theY-carboxylation of some of the glutamic acid residues in the protein.

The Y-carboxyl glutamic acid residues formed,bind with Ca+2 and are necessary for the action of the group of factors in the clotting process

7 Drugs Opposing Homeostasis By Dr Barakat Shahin ANTICOAGULANTS Anticoagulants may be used in the Rx and prophylaxis of disorders resulting from the blockade of blood vessels by intravascular clotting, i.e. formation of thrombi or emboli. Anticoagulants a. Parenteral — Heparin

b. Oral. i. Coumarin derivatives—Dicumarol, Warfarin sodium, Warfarin potassium ii. lndandione derivatives—Phenindione, Anisindione.

8 Drugs Opposing Homeostasis By Dr Barakat Shahin Heparin It is believed to cause anticoagulation, by accelerating with the formation of complexes between antithrombin-III and several proteases, involved with the coagulation cascade. This includes factors II, VII, IX, X, as well as thrombin. Antithrombin-III is an a-globulin, normally present in the blood, is an important controlling protein. It forms a complex with active serine proteases which interact with its arginine containing site. In absence of exogenous heparin, the complex forms very slowly. After combining with exogenous heparin, it potentiates the action up to 1000folds. Pharmacological actions of heparin 1. Apart from its effects on coagulation, heparin can cause.

2. Plasma clearing effect—After a fatty meal. Normally, after heavy fat ingestion, plasma becomes milky. This milkiness can be cleared up by heparin. Milkiness is caused by presence of excess triglycerides obtained from food fat. These triglycerides are hydrolyzed by lipoprotein lipase causing clearance of milkiness.

3. Reduction of aldosterone secretion.

4. Delay in wound healing

9 Drugs Opposing Homeostasis By Dr Barakat Shahin HHeparin Actions • Indirect acting - Activates plasma antithrombin III (AT III) • Heparin-AT III complex inactivates clotting factors - Xa, IIa, IXa, XIIa and XIIIa, but not VIIa (extrinsic pathway) – At low conc. Xa mediated conversion of Prothrombin to thrombin affected – Overall, Xa and IIa mediated conversion of fibrinogen to fibrin • AT III (suicide inhibitor) – binds to clotting factors slowly to form stable complex. Heparin enhances it by 1.Heaprin creates scaffolding to bind each (clotting factors) other with AT III 2.A specific polysaccharide in heparin binds to AT III and induce conformational changes – bindfactors

Inhibition of Xa needs only the 2nd mechanism (LMWH) - fondaparinuxs • IIa needs both the mechanism • Antiplatelet action: High doses prevents platelet aggregation prolongs Bleeding time • Lipaemic clearing • Pharmacokinetics: – Highly ionized, not absorbed orally – given IV (instant action) and SC (slow action) – Does no cross BBB and placenta – 100 U/kg dose half life is 1 Hr., but above this dose 1 – 4 Hrs – Should not with – Penicillin, hydrocortisone or tetracycline

10 Drugs Opposing Homeostasis By Dr Barakat Shahin Adverse effects: 1. Bleeding due to overdose – haematuria is 1st sign 2. Thrombocytopenia – aggregation of platelets 3. Hypersensitivity – urticaria, rigor, fever and anaphylaxis etc. 4. Alopecia and osteoporosis

• Contraindications: Bleeding disorders, Severe hypertension, GIT ulcer, Piles, SABE & malignancy, Ocular & neurosurgery, Chronic alcoholism, cirrhosis etc. • Aspirin and antiplatelet drugs - caution

11 Drugs Opposing Homeostasis By Dr Barakat Shahin 12 Drugs Opposing Homeostasis By Dr Barakat Shahin Dosage of Heparin • Unitage: Expressed in units as it is standardized by bioassay – variable molecular size • 1 mg = 120-140 U activity • Administered as IV bolus 5000-10,000 u followed by 1000 u /hr IV drip – adjusted with aPTT value – Pretreatment aPTT value and followed by 1.5 to 2.5 times during therapy • Alternate: 10,000-20,000 deep SC every 8 Hrly (fine needle) • Or, Low dose SC – 5000 SC 8-12 Hry before and after surgery to prevent DVT • Protamine Sulfate: Heparin antagonist – given IV (1mg = 100U) – cardiac and vascular surgery

13 Drugs Opposing Homeostasis By Dr Barakat Shahin Vitamin K Antagonist The action of vitamin K in promoting the synthesis of prothrombin and factors II, VII, IX and X is completely antagonized by a number of Coumarin and Indanedione derivatives. Vitamin K antagonists are known collectively as systemically acting or indirect acting anticoagulant. They cause a decrease in plasma levels of vitamin K dependent clotting factors and thereby reduce the coagulability of the blood.

14 Drugs Opposing Homeostasis By Dr Barakat Shahin 15 Drugs Opposing Homeostasis By Dr Barakat Shahin Many substances can dissolve an established clot in our body, like plasminogen activators.Two of them, tPA and urokinase are endogenous whereas streptokinase is exogenous. Tissue plasminogen activator (tPA) also called tPA. (Recombinant tPA). It is a naturally occurring substance, synthesized from vascular endothelium. Commercially, tPA is now prepared by DNA recombinant technology which can be used for therapeutic purposes. Normally, plasminogen as well as tPA are present in circulating blood, but as tPA has originally very weak action so that no plasmin is formed. Alter a clot is formed, both plasminogen and tPA bind with the clot, now the efficacy of tPA increases greatly → acts on the bound plasminogen much intensely and faster → formation of plasmin. tPA is a fibrin selective agent— (1) Heparin is usually givenconcomitantly to prevent reocclusion, (2) It is given in AMI, (3) Serious allergic reactions are virtually unknown, (4) On the whole, it appears to produce more bleeding disorders (hence more risky). Streptokinase is obtained from group C-b-hemolytic streptococci. It combines with plasminogen molecule and streptokinase plasminogen complex is formed. Streptokinase alone has no enzyme activity. In the form of a complex, it can act on both (1) Circulating plasminogen as well as. (2) Plasminogen in a clot. Therefore, tPA acts only on the plasminogen in clot. Therefore, tPA is “fibrin selective”, i.e. dissolves the clot but its action remains confined on the clot and clot alone, no systemic effects occurs. Whereas streptokinase also acts on circulating16 plasminogen, so it should produceDrugs more Opposing bleeding Homeostasis disorders. By Dr Barakat Shahin As Streptokinase is obtained from streptococcus, so it is a foreign protein. Most persons in their lifetime have had streptococcal infections causing antistreptococcal antibodies to appear. These antibodies can and does neutralize with the Streptokinase. There will be Two Fall Outs 1. Dose of Streptokinase should be high to overcome neutralization by the antibodies.

2. There can be allergic reaction when IV Streptokinase is given, urticarial anaphylaxis can develop with IV Streptokinase.

Urokinase is an enzyme obtained from fetal kidney. In many respect, it has similarity with Streptokinase. However, allergic reactions are less frequent and is usually mild

17 Drugs Opposing Homeostasis By Dr Barakat Shahin