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08.05.2015Pharmaceuticals
SOME IMPORTANT DRUGS
OZAN KIRMIZI 150611033
Each year, The FDA Center for Drug Evaluation and Research’s (CDER) approves hundreds of new medications, most of which are variations of previously existing products, such as important new dosage forms of already approved products, or cost-saving generic formulations.
Pharmaceuticals – Some Important Drugs
These new products contribute to quality of care, greater access to medication, more consumer choice, and a competitive marketplace that enhances affordability and public health.
Pharmaceuticals – Some Important Drugs
Novel new drugs are often innovative products that serve previously unmet medical needs or otherwise significantly help to advance patient care and public health.
Pharmaceuticals – Some Important Drugs
In some cases, while categorized as novel for technical and/ or administrative purposes, a particular novel new drug may not necessarily offer unique clinical advantages over existing therapies.
Pharmaceuticals – Some Important Drugs
Company 2010-2014 Approvals
AstraZeneca 10
GlaxoSmithKline 9
J&J 9
Boehringer-Ingelheim
9
Merck&Co 8
Hoffman-La Roche 8
Novartis 7
Pharmaceuticals – Some Important Drugs
2014
1 CHOLESTEROL DRUGS
Some Important Drugs
CHO
LEST
ERO
L D
RUG
SWhat is Cholesterol?
Cholesterol is a waxy fat carried through the bloodstream by lipoproteins.
Cholesterol Drugs
Low-density lipoproteins (LDL), stores cholesterol in bloodstream. BAD CHOLESTEROL.
High-density lipoproteins (HDL), regulates LDL and promotes excretion. GOOD CHOLESTEROL.
Cholesterol Drugs
Cardiovascular disease accounts for more deaths, about 30% globally, thanany other disease and the over-accumulation of cholesterol is known to play a central role in cardiovascular disease.
Cholesterol Drugs
In the United States populationolder than 19, 31,7 % have cholesterol levels higher than 190 mg/dL.
Turkey, 39,7 %
Cholesterol Drugs
Prescription drug use by drug class
Cholesterol Drugs
Cholesterol Synthesis
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase) converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. Human 3-hydroxy-3-methylglutaryl coenzyme A, also abbreviated as HMGR consists of a polypeptide chain of 888 amino acids. Acetyl-CoA condenses with acetoacetyl-CoA to form HMG-CoA reductase.
Cholesterol Drugs
Cholesterol Synthesis
Hydride transfer from NADPH (the reduced form of nicotinamide adeninedinucleotide phosphate) gives initially mevaldyl-CoA which then formsmevaldehyde. Another reduction with NADPH gives mevalonate.
Cholesterol Drugs
Mevalonate is converted in a series of biosynthetic steps to squalene whichin turn is converted to cholesterol.
Cholesterol Drugs
The formation of mevalonate is the rate-limiting step in cholesterol biosynthesis.
Drugs that inhibit HMG-CoA reductase are termed statins and are one of the most widely used types of prescription drugs
Cholesterol Drugs
Statins occupy the binding site of HMG-CoA thus blocking access of this substrate. All statins share this common mode of action but differ in their overall structural, biochemical, thermodynamic, and pharmokinetic properties which influences their efficacy.
Cholesterol Drugs
The first statins were launched by Merck with lovastatin (Mevacor®) in 1987.
Cholesterol Drugs
The success of Mevacor• Mevacor had the highest sales ever of any prescription medicine in the United
States in the first 12 months of its U.S. Marketing.
• While Merck did not release Mevacor’s sales figure for 1988, analysts estimated it at $260 million.
• Furthermore, as of October 1988, Merck officials stated that Mevacor had cornered 30% of all new prescriptions written for cholesterol-reducing drugs.
• Mevacor, which was currently a phenomenal product with sales in excess of $1 billion.
Cholesterol Drugs
Merck launched simvistatin (Zocor®) in 1991.
Cholesterol Drugs
While developing and testing Mevacor in the 1980's, Merck was aware of its competitors’ similar research into HMG Co A reductase enzyme inhibitors. Specifically, Merck recognized the threat of Bristol Myers Squibb’s soon-to-be-released Pravachol, based on Akira Endo’s 1976 discovery, as a more potent cholesterol reducer than Mevacor. Therefore, along with Mevacor, Merck had concurrently researched and developed Zocor, which is a more potent, synthetic form of Mevacor. Zocor had been FDA approved in December, 1991 and was ready to be released in 1992.
Cholesterol Drugs
Since 2006 in many countries, it is available as generic preparation. This has led to a decrease of the price of most statin drugs, and a reappraisal of the health economics of preventive statin treatment.
simvistatin (Zocor®)
Cholesterol Drugs
Lovastatin can be prepared by a fermentation process in the presence of a specific microorganism.
Lovastatin can be converted to simvistatin.
Hydrolysis of the ester followed by reclosure of the lactone gives the diol.
Cholesterol Drugs
Bristol-Myers launched pravastatin (Pravacol®) in 1991.
pravastatin (Pravacol®)
Cholesterol Drugs
pravastatin (Pravacol®)FDA approved generic pravastatin for sale in the United States for the first time on April 24, 2006. Generic pravastatin sodium tablets are manufactured by Biocon Ltd, India and TEVA Pharmaceuticals in Kfar Sava, Israel.
Cholesterol Drugs
atorvastatin calcium (Lipitor®)Pfizer commercialized atorvastatin calcium (Lipitor®) in 1997.
As measured by annual sales, Lipitor is the most successfuldrug in the history of the pharmaceutical industry.
Cholesterol Drugs
atorvastatin calcium (Lipitor®)Although atorvastatin was the fifth drug in the class of statins to be developed, clinical trials showed that atorvastatin caused a more dramatic reduction in LDL-C than the other statin drugs.
From 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug of all time, with more than US $ 125 billion in sales over approximately 14.5 years
Cholesterol Drugs
atorvastatin calcium (Lipitor®)Pfizer's patent on atorvastatin expired in November 2011.
Cholesterol Drugs
rosuvastatin calcium (Crestor®)Rosuvastatin calcium (Crestor®) is AstraZeneca’s top drug with $6.6 billion in annual sales.
Cholesterol Drugs
rosuvastatin calcium (Crestor®)Crestor is the fourth-highest selling drug in the United States, accounting for approx. $5.2 billion in sales in 2013.
First launched in 2003, sales of rosuvastatin were $129 million and $908 million in 2003 and 2004, respectively, with a total patient treatment population of over 4 million by the end of 2004.
Cholesterol Drugs
Cholesterol Drugs
Another treatment for cholesterol is niacin. The use of niacin predates the statins.
Niacin is also known as nicotinic acid or vitamin B3. The name, niacin comes from nicotinic acid and vitamin.
Niacin inhibits lipoprotein synthesis by preventing the secretion of very low density lipoprotein from the liver.
Cholesterol Drugs
Simvistatin manufacturers in Turkey
Cholesterol Drugs
Pravastatin manufacturers in Turkey
Cholesterol Drugs
atorvastatin calcium manufacturers in Turkey
Cholesterol Drugs
rosuvastatin calcium manufacturers in Turkey
2 HYPERTENSİON DRUGS
Some Important Drugs
Hypertension Drugs
Hypertension is a major risk factor for cardiovascular disease.
Common classes of medications for the treatment of hypertension are;
• angiotensin II receptor antagonists,• ACE inhibitors,• calcium channel blockers,• β-blockers, • diuretics
Hypertension Drugs
The renin angiotensin system is one of the most powerful regulators ofblood pressure.
Renin, an enzyme, is secreted by the kidney in response toa reduction in blood flow, blood pressure or sodium concentration.Angiotensin I is cleaved by angiotensin-converting enzyme (ACE) to angiotensin II, an octapeptide which in turn activates angiotensin II receptors. Inhibition of theaction of angiotensin II at the receptors prevents the increase in blood pressurecaused by this hormone–receptor interaction. Medications that controlblood pressure by inhibiting the action of angiotensin II at the receptors arein a class termed angiotensin II receptor blockers (ARBs).
Hypertension Drugs
losartan potassium (Cozaar®, Merck)
The first receptor antagonist was losartan potassium.
Losartan potassium is a prodrug and is converted in the liver to anactive metabolite. The term “prodrug” is used for an inactive substancewhich is metabolized in-vivo to an active form. In other words, it is a drugprecursor.
Hypertension Drugs
The group name sartan was coined and other sartans were developed.Several, such as valsartan (Diovan®, Novartis) and irbesartan (Avapro®,Bristol-Myers Squibb) retained the biphenyl substituted tetrazole ring oflosartan.
Hypertension Drugs
In an early synthesis, the tetrazole is formed by reacting the substituted benzonitrile with sodium azide in a 1,3-dipolar cycloaddition.
By protecting the tetrazole as the trityl derivative,the product is soluble in toluene and unreacted azide can be removed bywashing with aqueous base. The use of a bulky trityl group also alleviatedconcerns with exothermic decomposition of the unprotected tetrazole.
Benzylic bromination under radical conditions with N-bromosuccinimide wasfollowed by displacement of the bromide with the substituted imidazole.
The aldehyde is reduced to the alcohol, the trityl group cleaved under acidic conditions and then treatment with KOH gives losartan.
Losartan Synthesis
Hypertension Drugs
Losartan Synthesis
Hypertension Drugs
ACE inhibitors
Inhibition of ACE blocks the formation of angiotensin II which thereforeblocks the renin angiotensin system.
Medications that operate by this principle are in the class termed, ACE inhibitors.
ACE is a zinc-containing enzyme and the zinc ion catalyzes peptide cleavage from angiotensin I to angiotensin II.
ACE inhibitors bind to the zinc cation and therefore inhibitthe cleavage.
Hypertension Drugs
captopril (Capoten®, Par Pharmaceutica Companies, Inc)
The discovery of captopril came from an observation made in the 1960s that an extract of the venom of the Brazilian viper was a potent ACE inhibitor.
Hypertension Drugs
captopril (Capoten®, Par Pharmaceutica Companies, Inc)
The extract was a peptide, not suitable for oral administration. To find an orally active form, over the next decade,Squibb spent millions of dollars for research and clinical studies which led to FDA approval of captopril in the early 1980s.
Hypertension Drugs
Calcium channel blockers
Also known as calcium antagonists, are a class of hypertension drugs that inhibit the influx of calcium ions through the cellmembrane.
A decrease in calcium ions results in less contraction of the cardiacand vascular muscles. There is an increase in the diameter of the arteries.
This vasodilatation results in a lowering of the blood pressure.
Hypertension Drugs
nifedipine (Procardia®, Pfizer),The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with coronary artery disease who took nifedipine.
Hypertension Drugs
Beta blockers
They block beta-adrenergic receptors, preventing adrenaline (epinephrine) from stimulating these receptors.
In this manner, they slow the heart rate and reduce the force with which the heart muscle contracts, thereby Lowering blood pressure.
Hypertension Drugs
carvedilol (Coreg®, Glaxo SmithKline),Carvedilol is a non selective beta blocker/alpha-1 blocker used in the treatment of mild to severe congestive heart failure (CHF) and high blood pressure.
Hypertension Drugs
Hypertension Drugs
Diuretics
Diuretics increase the rate of urine formation. One common class of diuretics is the thiazide type represented by hydrochlorothiazide. The thiazides affect the renal tubular mechanisms of electrolyte reabsorption and therefore directly increase excretion of sodium and chloride ions.
Hypertension has been linked to high sodium ion content and diuretics areused to combat hypertension by decreasing sodium levels.
Hypertension Drugs
lisinopril-hydrochlorothiazide (Prinzide®, Merck)Is a combination of the drugs lisinopril, an ACE inhibitor, and hydrochlorothiazide, a diuretic. It is used to control hypertension.
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