1. 08.05.2015
Pharmaceuticals
SOME IMPORTANT DRUGS
OZAN KIRMIZI 150611033

2. 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.

3. 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.

4. 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.

5. 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.

7. 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

8. Pharmaceuticals – Some Important Drugs
2014

9. CHOLESTEROL DRUGS
Some Important Drugs

10. CHOLESTEROLDRUGS
What is Cholesterol?
Cholesterol is a waxy fat carried through the
bloodstream by lipoproteins.

11. Cholesterol Drugs
Low-density lipoproteins (LDL), stores cholesterol in
bloodstream. BAD CHOLESTEROL.
High-density lipoproteins (HDL), regulates LDL and
promotes excretion. GOOD CHOLESTEROL.

12. Cholesterol Drugs
Cardiovascular disease
accounts for more deaths,
about 30% globally, than
any other disease and the
over-accumulation of
cholesterol is known to
play a central role in
cardiovascular disease.

13. Cholesterol Drugs
In the United States population
older than 19, 31,7 % have cholesterol levels
higher than 190 mg/dL.
Turkey, 39,7 %

14. Cholesterol Drugs
Prescription drug use by drug class

15. 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.

16. Cholesterol Drugs
Cholesterol Synthesis
Hydride transfer from NADPH (the reduced form of nicotinamide adenine
dinucleotide phosphate) gives initially mevaldyl-CoA which then forms
mevaldehyde. Another reduction with NADPH gives mevalonate.

17. Cholesterol Drugs
Mevalonate is converted in a series of biosynthetic steps to squalene which
in turn is converted to cholesterol.

18. 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

19. 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.

20. Cholesterol Drugs
The first statins were launched by Merck with lovastatin (Mevacor®) in
1987.

21. 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.

22. Cholesterol Drugs
Merck launched simvistatin (Zocor®) in 1991.

23. 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.

24. 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®)

25. 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.

26. Cholesterol Drugs
Bristol-Myers launched pravastatin (Pravacol®) in 1991.
pravastatin (Pravacol®)

27. 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.

28. Cholesterol Drugs
atorvastatin calcium (Lipitor®)
Pfizer commercialized atorvastatin calcium (Lipitor®) in 1997.
As measured by annual sales, Lipitor is the most successful
drug in the history of the pharmaceutical industry.

29. 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

30. Cholesterol Drugs
atorvastatin calcium (Lipitor®)
Pfizer's patent on atorvastatin expired in November 2011.

31. Cholesterol Drugs
rosuvastatin calcium (Crestor®)
Rosuvastatin calcium (Crestor®) is AstraZeneca’s top drug with $6.6 billion
in annual sales.

32. 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.

33. Cholesterol Drugs

34. 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.

35. Cholesterol Drugs
Simvistatin manufacturers in Turkey

36. Cholesterol Drugs
Pravastatin manufacturers in Turkey

37. Cholesterol Drugs
atorvastatin calcium manufacturers in Turkey

38. Cholesterol Drugs
rosuvastatin calcium manufacturers in Turkey

39. HYPERTENSION DRUGS
Some Important Drugs

40. 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

41. 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 to
a 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 the
action of angiotensin II at the receptors prevents the increase in blood pressure
caused by this hormone–receptor interaction. Medications that control
blood pressure by inhibiting the action of angiotensin II at the receptors are
in a class termed angiotensin II receptor blockers (ARBs).

42. 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 an
active metabolite. The term “prodrug” is used for an inactive substance
which is metabolized in-vivo to an active form. In other words, it is a drug
precursor.

43. 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 of
losartan.

44. 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 by
washing with aqueous base. The use of a bulky trityl group also alleviated
concerns with exothermic decomposition of the unprotected tetrazole.
Benzylic bromination under radical conditions with N-bromosuccinimide was
followed 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

45. Hypertension Drugs
Losartan Synthesis

46. Hypertension Drugs
ACE inhibitors
Inhibition of ACE blocks the formation of angiotensin II which therefore
blocks 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 inhibit
the cleavage.

47. 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.

48. 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.

49. 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 cardiac
and vascular muscles. There is an increase in the diameter of the
arteries.
This vasodilatation results in a lowering of the blood pressure.

50. 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.

51. 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.

52. 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.

53. Hypertension Drugs

54. 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 are
used to combat hypertension by decreasing sodium levels.

55. 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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