NSAIDs or Non-Steroidal Anti Inflammatory Drugs include a variety of drugs that are used to treat pain and inflammation.

They react through both selective and non selective mechanisms Recent data shows that NSAIDs can be used to induce apoptosis or inhibit tumor cell growth in colon cancer cells Colon cancer is one of the most common forms of cancer and successful treatment occurs with early detection of cancer cells NSAIDs helps prevent and treat colon cancer by 2 pathways: 1) COX dependent 2) COX independent COX 1 is constitutively expressed and mainly responsible for gastric mucosal lining and thromboxane production for platelet aggregation; COX 2 is induced during inflammation and involved in up-regulation of inflammatory responses and proliferation of colon cancer tissues Non-selective COX inhibitors may lead to gastrointestinal adverse effects due to destruction of stomach lining; selective COX 2 inhibitors such as Celecoxib may lead to cardiovascular adverse effects due to increased platelet formation Overall selective COX 2 inhibitors are more ideal chemopreventative drugs The cell cycle is closely mediated by cyclin and cyclin-dependent kinases (Cdks) forming complexes and undergoing degradation to meet specific check point requirements of their respective phases There is a global effect of NSAIDs by targeting these cyclin-cdk complexes to inhibit their activity on cyclindependent kinase inhibitor such as p21 Ultimately, NSAIDs possess the ability to push cells into quiescence bringing about cell cycle arrest in uncontrolled proliferation of cells in colon cancer At high doses, NSAIDs have shown to help reduce the risk/development of colon cancer through COXindependent mechanisms Three most prominent types of side effects of NSAIDs, in descending order, are gastrointestinal, cardiovascular, and renal NSAIDs can be used to lower the risk/severity of colon cancer via primary prevention, secondary prevention, as well as adjuvant therapy

Atheroschlerosis and foam cells

Atherosclerosis build up of plaque in the walls of elastic and muscular arteries Risk factors age, gender, family history, smoking, hypertension, hyperlipidemia etc. Can lead to myocardial infarction (heart attack) or cerebral infarction (stroke) Atherogenesis: Injury to endothelial cells Increase in permeability of lipid into intima VCAM-1 expression by the endothelial cells Monocytes migrate into intima engulf oxidized lipid to become foam cells Smooth muscle cell (SMC) migration into intima also become foam cells Fatty streak, the earliest grossly identifiable lesion, forms Intimal SMC emigration and proliferation continues SMC elaborate collagen which forms fibrous cap Progressive lipid accumulation Rupture of plaque may lead to thromboembolism Drugs for the treatment of atherosclerosis include antiplatelets, cholesterol lowering drugs, and blood pressure lowering drugs Angioplasty is the process of inserting a deflated balloon into a blood vessel and inflating it in order to widen the artery.

Anticoagulant and Vit K

Vitamin K dependent Clotting Factors: II (Prothrombin), VII, IX, X Three forms of Vitamin K: 1) Vitamin K, 2) Vitamin K Hydroquinone (KH2) 3) Vitamin K Epoxide (KO) KH2 converts Glutamic Acid residues into carboxyglutamic acid (necessary for clotting factor formation) via -glutamyl carboxylase. Warfarin strongly inhibits Vitamin K Epoxide Reductase (reduces KO into Vitamin K), resulting in anticoagulation effect. Excess exogenous dose of Vitamin K can be used to reverse Warfarin toxicity.

Durg induced fatty liver

Fatty liver is accumulation of fat in the liver It can be induced through many factors, including drugs and alcohol No well treatment is known, and if not taken care of it can cause severe consequences such as cirrhosis Mechanisms that cause fatty liver Chemically reactive drug metabolites can:
Inhibit mitochondrial respiration b-oxidation of fatty acids VLDL secretion by the liver

Anti-psychotics can cause insulin resistance leading to increase FFA release from the adipocytes and de novo synthesis of FFAs in the liver Insulin may also be associated with decreased fatty oxidation and decreased VLDL secretion

Dietary ways to decrease blood cholesterol

precursor: bile acids, steroid molecules and vitamin D Proteins facilitate absorption in small intestine: SR-B1, NPC1L1, ACAT Travel in blood stream as lipoproteins High cholesterol: atherosclerosis, heart attack, stroke -glucan, a type of soluble fibre, binds bile acid in the intestine to inhibit cholesterol absorption and bile acid reabsorption Unsaturated fat lower cholesterol by increasing cholesterol oxidation to bile acid and increase LDL catabolism Unsaturated fat are found in vegetable oil, nuts. Omega-3 oils are found in fish and flaxseed EGCG is a major catechin found in green tea extracts that inhibits lipid hydrolysis, absorption and intestinal uptake. Cholesterol absorption is significantly reduced if caffeine was used concordantly with EGCG. Green teat extracts also inhibit cholesterol synthesis in hepatoma cells by downregulating the activity of HMG-CoA by AMP-kinase.

Drugs that cause lethal cholestasis

Bile is an exocrine secretion of hepatocytes Most potent stimulus for bile secretion is its own presence in enterohepatic circulation Itching is the primary symptom of cholestasis The rate limiting step of bile formation is transport of constituents across the canalicular membrane BSEP, MRP1-3, and MDR2 are the transporters most likely to be involved in the pathophysiology of cholestasis Cyclosporine reduces MRP2 activity, leading to bile saltindependent bile flow Bosentan inhibits BSEP, reducing bile salt-dependent canalicular secretion

Macrophage infiltraion
Monocytes differentiate, in the tissue, into macrophages Macrophages upon activation will release various cytokines including IL-8 and TNF Macrophage Infiltration: 1. Upon a stimulus, ICAM1/2 and P/E selectins are upregulated on cell surface 2. Selectins bind to sulfated-sialyl-Lewisx moieties on monocytes 3. Mac-1 and LFA-1 bind weakly to ICAM-1 and ICAM-2 respectively 4. Il-8 binds to Il-8 receptor, triggers conformation change in Mac-1 and LFA-1, now binds strongly to their ligands 5. Monocyte moves laterally across endothelium 6. Monocyte crosses endothelial wall via interaction of CD31 and CD99, known as diapedesis 7. Enters subepithelial tissue by breaking down basement membrane

Kuppfer cell activation

Kupffer cells: resident liver macrophages Endotoxins: found on cell wall of Gram-negative bacteria Endotoxin binds to CD14 and TLR4 receptors on the Kupffer cells Activation of Kupffer cells generates cytokines and superoxides The activation of Kupffer cells by endotoxin has been shown to be involved in alcoholic liver injury Further research into TLRs and Kupffer cell activation may lead to promising therapies for liver disease