Platelet Aggregation and Plug Formation

• Platelet aggregation contributes to the clotting process
• Platelets play a central role in clots in the arterial circulation
• Platelet aggregation is triggered by Prostaglandin, Thromboxane, Adenosine Diphosphate (ADP), Thrombin, and Fibrin
• Intracellular cyclic adenosine monophosphate (cAMP) such as Prostacyclin and Adenosine inhibit platelet aggregation

Platelet Plug Formation

• Step 1: Platelet Adhesion
• Step 2: Platelet Activation
• Step 3. Platelet Aggregation

Platelet Adhesion

• Damage to blood vessel endothelium exposes subendothelial collagen
• A glycoprotein called von Willebrand factor is released by damaged endothelial cells and binds to the exposed collagen
• The circulating intravascular platelets have a receptor called glycoprotein (GP) Ib that binds the von Willebrand factor, GP 1a that is bound to the collagen

Platelet Activation

• Activation of platelets leads to degranulation into the intravascular space
• Contents include cytokines, ADP, thromboxanes A2, vWF, platelet-activating factor (PAF), vascular endothelial growth factor (VEGF), coagulation factors, serotonin, other chemical mediators
• Thromboxane and serotonin serve as vasoconstrictors to reduce bleeding

Platelet Aggregation

• Platelets adhere and become activated at injury site to bind and strengthen the platelet plug
• Activated platelets express GPIIb/IIIa receptors that bind fibrinogen to cross-link platelets
• Results in solidifying and strengthening the platelet plug

Classification of Antiplatelet Drugs

• Cyclooxygenase (COX) inhibitors e.g., Aspirin
• Glycoprotein IIb/IIIa receptor inhibitors e.g., Abciximab, Tirofiban, and Eptifibatide
• ADP receptors antagonists e.g., Clopidogrel, Prasugrel, and Ticlopidine
• Inhibitors of phosphodiesterase 3 e.g., Dipyridamole and Cilostazol

Aspirin

• Mechanism of Action: inhibits thromboxane synthesis by blocking cyclooxygenase (COX)
• Thromboxane A2 is a potent stimulator of platelet aggregation
• Aspirin is an irreversible COX inhibitor
• Inhibition persists for days until new platelets are formed, because platelets lack the machinery for synthesis of new protein

Clinical Uses for Aspirin

• Used to prevent further myocardial infarcts and may reduce incidence of first infarcts
• Used to prevent transient ischemic attacks (TIAs), stroke, and other thrombotic events

Adverse Effects & Toxicity from Aspirin

• All antiplatelet drugs enhance effects of other anticlotting agents
• Aspirin and NSAIDs cause gastrointestinal and CNS effects

Glycoprotein IIb/IIIa Receptor Inhibitors

• Abciximab, Eptifibatide, and Tirofiban
• Reversibly inhibit the binding of fibrinogen to the platelet glycoprotein IIb/IIIa receptor (involved in platelet cross-linking)
• Abciximab is a monoclonal antibody
• Clinical Uses: Prevent restenosis after coronary angioplasty, for acute coronary syndromes such as unstable angina and acute myocardial infarction
• Toxicities are bleeding and thrombocytopenia (with chronic use)

ADP Receptor Antagonists

• Clopidogrel, Prasugrel, and Ticlopidine
• Clopidogrel, Prasugrel, and Ticlopidine are converted to active metabolites in the liver to irreversibly inhibit the platelet ADP receptor
• Ticagrelor is a newer drug that does not require activation and reversibly inhibits the platelet ADP receptor
• Clinical uses: Are effective in preventing Transient Ischemic Attacks and strokes if patients cannot tolerate Aspirin, and used to prevent thrombosis in patients who have received a coronary artery stent
• Adverse effects and toxicities: Ticlopidine is rarely used, as it causes bleeding (up to 5% of patients), severe neutropenia (about 1%), and thrombotic thrombocytopenic purpura (very rare)
• Clopidogrel is less hematotoxic

Inhibitors of Phosphodiesterase III

• Dipyridamole and Cilostazol
• Dipyridamole and Cilostazol have a dual mechanism of action
• Prolong the action of intracellular cAMP by inhibiting PDE that degrades cAMP (which is an inhibitor of platelet aggregation)
• Inhibit the uptake of adenosine by endothelial cells and erythrocytes
• Increase plasma concentration of Adenosine, which activates platelet adenosine A₂ receptors to increase platelet cAMP and inhibit aggregation
• Clinical uses: Dipyridamole is approved as an adjunct to Warfarin for thrombosis prevention in patients with cardiac valve replacement
• Dipyridamole is used in combination with Aspirin for secondary prevention of ischemic stroke
• Cilostazol is used to treat intermittent claudication, a manifestation of peripheral arterial disease
• Adverse effects and toxicity: Common adverse effects of Dipyridamole and Cilostazol are headaches and palpitations
• Cilostazol is contraindicated in patients with congestive heart failure due to evidence of reduced survival

Drugs Used in Bleeding Disorders

• Inadequate blood clotting is from Vitamin K deficiency, genetically determined errors of clotting factor synthesis such as hemophilia, and thrombocytopenia
• Treat with Vitamin K, fresh plasma and purified human blood clotting factors, factor VIII (for hemophilia A) and factor IX (for hemophilia B)
• Can use Antiplasmin drugs, platelets or Oprelvekin recombinant form of Megakaryocyte growth factor Interleukin-11

Vitamin K

• Deficiency of vitamin K (Fat-soluble) is common in persons with abnormalities of fat absorption and in newborns
• Newborns are at risk of bleeding due to vitamin K deficiency
• Treat deficiency with oral or parenteral vit K1
• In some countries, all newborns receive an injection of vit K1
• Large doses of vit K1 reverse the effect of excess Warfarin

Antiplasmin Agents

• Aminocaproic acid and Tranexamic acid
• Orally active agents
• Mechanism of Action: Inhibit fibrinolysis by inhibiting plasminogen activation
• Uses: For acute bleeding episodes in patients with Hemophilia and others with a risk of bleeding disorders
• Adverse effects: Thrombosis, Hypotension, Myopathy, and Diarrhea

Drugs Used for the Treatment of Hyperlipidemia

• Plasma lipid is transformed in complex called lipoprotein
• Lipoprotein is Spherical macromolecular complexes of lipids and specific protein ( Apo-protein ) that transport fats within the body
• Metabolic disorders that involved elevation in any lipoprotein species are called Hyperlipidemia or hyperlipoproteinemia

Clinical aspects for Hyperlipidemia

• Atherosclerosis premature or accelerated development is associated with elevated concentrations of certain plasma lipoproteins, especially low-density lipoproteins (LDLs) and a low depressed level of high-density lipoproteins (HDLs)
• Acute pancreatitis is associated with hyperlipidemia

Plasma Lipids

• Lipids, are water insoluble and cannot be transported in plasma on their own
• Lipids are conjugated to proteins to from lipoprotein to become water soluble and can transport in the plasma
• These proteins are synthesized by the liver and intestine, and called Apolipoproteins (Apo-Protein)
• There are six classes of ( A, B, C, D, E and H)

Lipoprotein types and Function

• Chylomicrons carry triglycerides from the intestines to the liver, peripheral extrahepatic tissues, skeletal muscle, and adipose tissue (heart)
• VLDL, carry endogenous lipids from the liver to heart and skeletal muscle
• LDL - carry Cholesterol to extrahepatic tissues
• HDL - Reverse Cholesterol transport

Hyperlipidemia Overview

• Desired values for serum cholesterol, HDL, and LDL:

Lipid|Desired values

• --|--- Total Serum Cholesterol| <200mg/dL HDL Cholesterol| 40-50mg/dL for men and 50-60mg/dL for woman LDL Cholesterol| <100mg/dL Triglycerides| <150mg/dL

Treatment of Hyperlipidemia

• To modify hepatic cholesterol synthesis (hepatic hydroxy-methylglutaryl coenzyme A {HMG-CoA} reductase inhibitors) the statins, Simvastatin, Lovastatin can be used
• To reduce bile absorption from intestine the bile acid sequestrants of, Cholestyramine, Colesevelam, Colestipol can be used
• Use Ezetimibe to Reduce cholesterol absorption from intestine:
• Decrease secretion of lipoproteins with Niacin (nicotinic acid, Vitamin B3)
• Increase peripheral clearance of lipoproteins: with, Gemfibrozil, Fenofibrate, Clofibrate

HMG-CoA reductase inhibitors

• Prodrugs are Simvastatin and Lovastatin
• Active drugs are Atorvastatin, Pravastatin, Pluvastatin
• They Lower cholesterol by inhibiting the enzyme HMG-CoA reductase, this is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis in the liver
• Reductase inhibitor increases in LDL receptors (to reduce LDL from the blood)
• These cause Small decreases in plasma triglycerides and a slight increase in HDL
• Directly have an antiatherosclerotic effect
• Prevent bone loss
• Can be used for cases of elevated LDL
• Women who are Pregnant cannot take this medication as it causes teratogenicity
• Side effects include an increase in creatinine kinase (skeletal muscles)
• Reductase inhibitor-induced myopathy is more likely with with drugs Cyclosporine, Azole antifungal drugs, Macrolide antibiotics, and Niacin
• frequent measures of creatinine kinase activity is recommended

Resins

• Cholestyramine, Colesevelam, Colestipol
• Bile acids, and cholesterol are 95% reabsorbed in the jejunum and ileum
• These cause excretion increases up to 10X .
• Increased bile acid clearance causes increased conversion of cholesterol to bile acids in the liver resulting in compensatory increase in the LDL reducing the levels in the blood
• Very little effect on HDL and or triglycerides.
• Used in patients with hypercholesterolemia and to reduce pruritus in patients with cholestasis and bile salt accumulation
• Side effects are Bloating, Constipation, and or Unpleasant gritty taste.
• Reduces the amount of Vitamins and drugs such as Digitalis, Statins and Warfarin
• Can be used in with patients who hypercholesterolemia

Ezetimibe

• Prodrug converted in the liver to active glucuronide form.
• Prevents GIT uptake of dietary cholesterol.
• Compensatory increase in the high affinity LDL receptors increases the removal of LDL from the blood.
• Can be used for patients with hypercholesterolemia
• Can cause increased risk of liver toxicity when combined with HMG-CoA reductase inhibitors

Niacin (nicotinic acid, Vitamin B3)

• The VLDL reduces secretion is decreases LDL production
• These increase the VLDL lipoprotein lipase.
• Decreased cholesterol synthesis
• Decreased levels of serum triglyceride and HDL that cause elevated cholesterol in plasma levels
• Wide range to treat hyperlipidemia cases
• toxicity causes Cutaneous vasodilation with a sensation of warmth
• Taking an Aspirin pre-treatment (30 minutes before dosing) or Ibuprofen (once daily) reduce it
• Acanthosis appearance is a side effect
• Avoid Niacin with patients with severe peptic disease.
• Can cause Hyperuricemia so allopurinol is given
• Can cause Hypotension that hypertensive medication increases

Fibrates (gemfibrozil, fenofibrate, Clofibrate)

• work to Increase lipoprotein triglyceride lipolysis through lipoprotein lipase action
• reduce serum triglyceride levels
• used to treat Hypertriglyceridemia if (VLDL predominates)
• Toxicity for causes Gastrointestinal upset, myopathy, arrhythmias, skin rashes
• Avoid patients who have hepatic or renal dysfunction
• causes Slight increase in gallstone incidence

Drug Combination Treatments

• Gemfibrozil and Resins May be useful for patients with familial combined hyperlipidemia who are intolerant to niacin but have high cholelithiasis risk
• HMG-CoA Reductase inhibitor and Bile Acid-Binding Resin work well together for cases of familial hypercholesterolemia
• these cause increased VLDL for patients with familial combined hyperlipidemia
• Niacin and Bile Acid works for patients who have familial combined hyperlipidemia and colestipol to treat familial hypercholesterolemia
• Niacin and HMG-CoA are the most effective combination for patients with familial combined hyperlipidemia
• Resin, Niacin, and HMG-CoA are used to treat patients with high LDL