litelatur R2

7/25/2019 litelatur R2

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Asam asetil salisilat :The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic

properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Acetylsalicylic acid

also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. (From Martindale, The Extra Pharmacopoeia,

30th ed, p5)

Indication For use in the temporary relief of various forms of pain, inflammation associated with various conditions (including rheumatoid

arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and ankylosing spondylitis), and is also

used to reduce the risk of death and/or nonfatal myocardial infarction in patients with a previous infarction or unstable angina

pectoris.

Pharmacodynamics Acetylsalicylic acid is an analgesic, antipyretic, antirheumatic, and anti-inflammatory agent. Acetylsalicylic acid's mode of action

as an antiinflammatory and antirheumatic agent may be due to inhibition of synthesis and release of prostaglandins.

Acetylsalicylic acid appears to produce analgesia by virtue of both a peripheral and CNS effect. Peripherally, acetylsalicylic acidacts by inhibiting the synthesis and release of prostaglandins. Acting centrally, it would appear to produce analgesia at a

hypothalamic site in the brain, although the mode of action is not known. Acetylsalicylic acid also acts on the hypothalamus to

produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow. Acetylsalicylic

acid's antipyretic activity may also be related to inhibition of synthesis and release of prostaglandins.

Mechanism of action The analgesic, antipyretic, and anti-inflammatory effects of acetylsalicylic acid are due to actions by both the acetyl and the

salicylate portions of the intact molecule as well as by the active salicylate metabolite. Acetylsalicylic acid directly and

irreversibly inhibits the activity of both types of cyclooxygenase (COX-1 and COX-2) to decrease the formation of precursors of

prostaglandins and thromboxanes from arachidonic acid. This makes acetylsalicylic acid different from other NSAIDS (such asdiclofenac and ibuprofen) which are reversible inhibitors. Salicylate may competitively inhibit prostaglandin formation.

Acetylsalicylic acid's antirheumatic (nonsteroidal anti-inflammatory) actions are a result of its analgesic and anti-inflammatory

mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation. The platelet aggregation-inhibiting effect of

acetylsalicylic acid specifically involves the compound's ability to act as an acetyl donor to cyclooxygenase; the nonacetylated


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salicylates have no clinically significant effect on platelet aggregation. Irreversible acetylation renders cyclooxygenase inactive,

thereby preventing the formation of the aggregating agent thromboxane A2 in platelets. Since platelets lack the ability to

synthesize new proteins, the effects persist for the life of the exposed platelets (7-10 days). Acetylsalicylic acid may also inhibit

production of the platelet aggregation inhibitor, prostacyclin (prostaglandin I2), by blood vessel endothelial cells; however,

inhibition prostacyclin production is not permanent as endothelial cells can produce more cyclooxygenase to replace the non-functional enzyme.

Absorption Absorption is generally rapid and complete following oral administration but may vary according to specific salicylate used,

dosage form, and other factors such as tablet dissolution rate and gastric or intraluminal pH.

Volume of distribution Not Available

Protein binding High (99.5%) to albumin. Decreases as plasma salicylate concentration increases, with reduced plasma albumin concentration

or renal dysfunction, and during pregnancy.

Metabolism Acetylsalicylic acid is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated with glycine (forming

salicyluric acid) and glucuronic acid and excreted largely in the urine.

Name Clopidogrel

Accession Number DB00758(APRD00444)


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Type Small Molecule

Groups Approved, Nutraceutical

Description Clopidogrel, an antiplatelet agent structurally and pharmacologically similar to ticlopidine, is used to inhibit blood clots in a variety of

conditions such as peripheral vascular disease, coronary artery disease, and cerebrovascular disease. Clopidogrel is sold under the

name Plavix by Sanofi and Bristol-Myers Squibb. The drug is an irreversible inhibitor of the P2Y12 adenosine diphosphate receptor

found on the membranes of platelet cells. Clopidogrel use is associated with several serious adverse drug reactions such as severe

neutropenia, various forms of hemorrhage, and cardiovascular edema.

Pharmacology

Indication For the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis

documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.

Pharmacodynamics Since clopidogrel is a prodrug, it must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet

aggregation. This active metabolite selectively inhibits adenosine diphosphate (ADP) binding to its platelet P2Y12 receptor and

subsequently the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

Mechanism of action The active metabolite of clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-

mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the

storage sites of the platelet granules to the outer membrane. he drug specifically and irreversibly inhibits the P2Y12 subtype of ADP

receptor, which is important in aggregation of platelets and cross-linking by the protein fibrin. No direct interference occurs with the

GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents


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fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP,

platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of clopidogrel.

Absorption Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Bioavailability has not been found to beaffected by food.

Volume of distribution Not Available

Protein binding 98%

Metabolism Hepatic, extensive and rapid, by hydrolysis to the main circulating metabolite, a carboxylic acid derivative, which accounts forapproximately 85% of the circulating drug-related compounds. A glucuronic acid derivative of the carboxylic acid derivative has also

been found in plasma and urine. Neither the parent compound nor the carboxylic acid derivative has a platelet inhibiting effect.

Substrate Enzymes Product

Clopidogrel

Cytochrome P450 3A4

Cytochrome P450 3A5

Cytochrome P450 2C9

2-Oxoclopidogrel
http://www.drugbank.ca/biodb/bio_entities/BE0002638http://www.drugbank.ca/biodb/bio_entities/BE0002362http://www.drugbank.ca/biodb/bio_entities/BE0002793http://www.drugbank.ca/metabolites/DBMET00098http://www.drugbank.ca/biodb/bio_entities/BE0002362http://www.drugbank.ca/biodb/bio_entities/BE0002793http://www.drugbank.ca/metabolites/DBMET00098http://www.drugbank.ca/biodb/bio_entities/BE0002638


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Cytochrome P450 2C19

Cytochrome P450 1A2

Cytochrome P450 2B6

Description ROSUVASTATINis an antilipemic agent that competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA)

reductase. HMG-CoA reducuase catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in

cholesterol biosynthesis. Rosuvastatin belongs to a class of medications called statins and is used to reduce

plasma cholesterol levels and prevent cardiovascular disease.

Pharmacology

Indication Used as an adjunct to dietary therapy to treat primary hyperlipidemia (heterozygous familial and nonfamilial), mixed

dyslipidemia and hypertriglyceridemia. Also indicated for homozygous familial hypercholesterolemia as an adjunct

to other lipid-lowering therapies or when other such therapies are not available. Furthermore, it is used to slow the

progression of atherosclerosis and for primary prevention of cardiovascular disease.

Pharmacodynamics Rosuvastatin is a synthetic, enantiomerically pure antilipemic agent. It is used to lower total cholesterol, low density

lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and
http://www.drugbank.ca/biodb/bio_entities/BE0003536http://www.drugbank.ca/biodb/bio_entities/BE0002433http://www.drugbank.ca/biodb/bio_entities/BE0003549http://www.drugbank.ca/biodb/bio_entities/BE0003536http://www.drugbank.ca/biodb/bio_entities/BE0002433http://www.drugbank.ca/biodb/bio_entities/BE0003549


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trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG

concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The

total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with

higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-

C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality.

Mechanism of

action

Rosuvastatin is a competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the conversion of

HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Rosuvastatin acts primarily in the

liver. Decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein

(LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low

density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL. In vitro and in vivo animal

studies also demonstrate that rosuvastatin exerts vasculoprotective effects independent of its lipid-lowering

properties. Rosuvastatin exerts an anti-inflammatory effect on rat mesenteric microvascular endothelium by

attenuating leukocyte rolling, adherence and transmigration (PMID: 11375257). The drug also modulates nitric

oxide synthase (NOS) expression and reduces ischemic-reperfusion injuries in rat hearts (PMID: 15914111).

Rosuvastatin increases the bioavailability of nitric oxide (PMID: 11375257, 12031849, 15914111) by upregulating

NOS (PMID: 12354446) and by increasing the stability of NOS through post-transcriptional polyadenylation (PMID:

17916773). It is unclear as to how rosuvastatin brings about these effects though they may be due to decreased

concentrations of mevalonic acid.

Absorption Bioavailability is approximately 20%. Peak plasma concentrations were reached 3 to 5 hours following oral dosing.

Both Cmax and AUC increased in approximate proportion to CRESTOR dose. Food has no effect on the AUC ofrosuvastatin.


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Volume of

distribution 134 L [steady-state]

Protein binding 88% bound to plasma proteins (mostly albumin). Binding is reversible and independent of plasma concentrations.

Metabolism Not extensively metabolized. Only ~10% is excreted as metabolite. Cytochrome P450 (CYP) 2C9 is primarily

responsible for the formation of rosuvastatin's major metabolite, N-desmethylrosuvastatin. N-desmethylrosuvastatin

has approximately 50% of the pharmacological activity of its parent compound in vitro. Rosuvastatin clearance is

not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. Rosuvastatin accounts for

greater than 90% of the pharmacologic action. Inhibitors of CYP2C9 increase the AUC by less than 2-fold. This

interaction does not appear to be clinically significant.


Ros!"st"ti#

Cytochrome P450 2C9

Ros!"st"ti# 5 S-l"cto#e $et"ils

Ros!"st"ti#

Cytochrome P450 2C9

Cytochrome P450 2C19

N-$esmethylros!"st"ti# $et"ils

Route of

elimination

Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite.

Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). After an

intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.
http://www.drugbank.ca/biodb/bio_entities/BE0002793http://www.drugbank.ca/metabolites/DBMET00216http://www.drugbank.ca/metabolites/DBMET00216http://www.drugbank.ca/metabolites/DBMET00216http://www.drugbank.ca/reactions/217http://www.drugbank.ca/biodb/bio_entities/BE0002793http://www.drugbank.ca/biodb/bio_entities/BE0003536http://www.drugbank.ca/metabolites/DBMET00217http://www.drugbank.ca/metabolites/DBMET00217http://www.drugbank.ca/reactions/218http://www.drugbank.ca/biodb/bio_entities/BE0002793http://www.drugbank.ca/metabolites/DBMET00216http://www.drugbank.ca/reactions/217http://www.drugbank.ca/biodb/bio_entities/BE0002793http://www.drugbank.ca/biodb/bio_entities/BE0003536http://www.drugbank.ca/metabolites/DBMET00217http://www.drugbank.ca/reactions/218


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Half life 19 hours

Clearance Not Available

Toxicity Generally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea.

Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid

toxicity in Asian patients, lower doses should be considered. Pharmacokinetic studies show an approximately two-

fold increase in peak plasma concentration and AUC in Asian patients (Philippino, Chinese, Japanese, Korean,

Vietnamese, or Asian-Indian descent) compared to Caucasians patients.

Usual Geriatric Dose for Hyperlipidemia

Initial dose: 5 mg once a day with or without food

Maintenance dose: 5 mg to 20 mg once a day with or without food

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