????(?) -New Drugs of 2001-2004 Review-

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????(?)-New Drugs of 2001-2004 Review-

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• ???????????

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• ?????,??????
• New Antihypertensive Agents
• Olmesartan
• Eplerenone
• New agents for Dyslipidemia
• Ezetimibe
• Rosuvastatin
• New Drugs for Treating Asthma/COPD
• Formoterol

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• Part I
• Antihypertensive agents
• Antihyperlipidemic agents
• Agents for asthma and COPD

• Part II
• Antihyperglycemics
• Agents for migraine
• Agents for impotence

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• Part III
• Antimicrobials
• Anticonvulsants
• Agents for Parkinsons disease

• Part IV
• COX II inhibitors
• Agent for treating psychosis
• Agents for osteoporosis
• Agents for peptic ulcer

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• Part V
• Herbs or natural products that may cause cancer
  and harm
• Herbs that increase cancer growth and recurrence

• Part VI
• Cancer prevention
• preventing tabacco-related cancer
• Diet
• chemopreventive agents
• surgery
• Cancer screening

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New Antihypertensive Agents
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Olmesartan

• Olmesartan
• Pharmacology
• Angiotensin receptor blocker (ARB)
• Selective antgonism of the angiotensin II type I
  receptor (AT1)
• Comparison chart
• rapidly and completely de-esterified in the gut
• active metabolite, olmesartan, in a reaction that
  is not dependent on cytochrome P450
• prolonged terminal elimination of 1218 hours,
  which is longer than most other AT1 receptor
  antagonists
• T/P ratio
• should have a troughpeak ratio that consistently
  exceeds 60
• the evidence suggests that blood pressure control
  is sustained well beyond the dosage interval,
  providing 'cover' for the poorly compliant
  patient.

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Olmesartan

• Olmesartan
• Adverse effects
• The most commonly reported ADR
• Headache (7.2 vs. 5.6 placebo)
• Upper respiratory infection (4.9 vs. 3.3placebo)
• Precautions
• Unilateral or bilateral renal artety stenosis
  have had increases in serum creatinine or BUN
  after administration of drugs (ACEIs and ARBs)
• Drug interactions
• Antacids decrease olmesartans bioavailability
• Dosage/administration
• Initially, 20 mg QD
• Dose increased to 40 mg if no response is seen in
  the first 2 weeks
• gt 40 mg, no additional benefit at higher doses

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Olmesartan????ARB??????
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Olmesartan

• Comparison between ARBs
• Blood pressure lowering effects
• Olmesartangt irbesartangt losartangt valsartan
• FDA approved indications
• Losartan (Cozaar ?????)
• Essential hypertension
• Provides renoprotective effect in patients with
  type 2 diabetes mellitus
• hypertensive patients with left ventricular
  hypertrophy for reduction of the risk of stroke

• FDA approved indications (cont.)
• Valsartan(Diovan ??)
• CHF
• Essential hypertension
• Irbesartan (Aprovel???)
• Essential hypertension
• Provides renoprotective effect in patients with
  type 2 diabetes mellitus
• Candesartan (Blopress??)
• Essential hypertension
• Telmisartan (Micardis ??????)
• Essential hypertension
• Olmesartan (Olmetec ??)
• Essential hypertension
• Eprosartan (?????)
• Essential hypertension

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ARB ?ACEI??????
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ACEIs vs. ARBs

• Cardiovascular protection in high-risk
  populations with cardiac disease and/or diabetes
• ACEIARB
• ARB are associated with less adverse side
  effects and with higher compliance
• Renoprotective in type 1 diabetes
• Only ACEI

• Preventing progression from microalbuminuria to
  overt albuminuria in type 2 diabetes
• Both ACEI and ARB
• ARB can prevent loss of GFR
• ACEI can prevent loss of GFR?
• Side effects
• ARBs cause less cough
• ARBs cuase less angioedema

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Eplerenone

• Eplerenone
• Pharmacology
• A competitive antagonist of the aldosterone
  receptor (potassium sparing diuretic)
• A chemical derivative of spironolactone
• enhance selective binding to the
  mineralocorticoid receptor
• minimizing binding to progesterone and androgen
  receptors, which may lead to adverse effects

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Eplerenone

• Eplerenone
• Pharmacology
• Aldosterone and cardiovascular injury
• Renin-angiotensin-aldosterone system (RAAS)
  regulates cardiovascular homeotasis
• Activation of RAAS
• Increases risk of ischemic cardiovascular events
• Drugs interrupt the RAAS
• Reduce the risk of cardiovascular events
• Preventing angiotensin IIs effects on
• cellular growth and proliferation
• vascular superoxide radical formation
• thrombotic pathway

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Eplerenone

• Eplerenone
• Pharmacology (cont.)
• Heart failure and Aldosterone
• a decrease in cardiac output
• an ischemic or non-ischemic insult to myocardial
  tissue
• activation of the RAAS and SNS
• in the short term for restoring cardiac output
• prolonged RAAS and SNS activation
• the progression of heart failure by increasing
  cardiac workload
• Chronic neurohormonal stimulation promotes
  ventricular hypertrophy and remodeling.
• Increases in circulating catecholamines and
  angiotensin II promote synthesis and release of
  aldosterone. (by adrenal gland, vasculature, and
  heart)

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Eplerenone

• Eplerenone
• Pharmacology (cont.)
• Elevated aldosterone plasma concentration
• Endothelial dysfunction
• Myocardial infarction
• Left ventricular hypertrophy
• Death
• ACEI and AT1 antagonist
• initially reduce aldosterone concentration,
• the aldosterone concentration return to baseline
  with chronic therapy
• Coadministration of spironolactone enhances the
  beneficial effects of ACEI on mortality in
  patient with CHF
• Aldosterone contributes to cardiovascular
  toxicity independent of the effects of
  angiotensin II

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Eplerenone

• Eplerenone vs. spironolactone
• Advantages of eplerenone
• the lack of altered absorption with food
• the absence of active metabolites.
• Disadvantage of eplerenone
• metabolism via the CYP3A4 pathway (potential for
  drug interactions)
• Adverse effects (chart)
• Drug interactions
• Hyperkalemia
• Potassium supplements
• ACEI or ARB
• Enzyme inhibitors or inducers
• Decrease antihypertensive effects
• NSAIDs

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The Seventh Report of the JointNational
Committee on Prevention, Detection,Evaluation,
and Treatment of High BloodPressure (JNC 7)

• JAMA. 2003 May 21289(19)2560-72 (express
  version)
• Hypertension. 2003 Dec42(6)1206-52 (complete
  version)

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Outline of JNC 7

• Introduction
• Lifetime risk of hypertension
• Blood pressure and cardiovascular risk
• Basis for reclassification of blood pressure
• Importance of systolic blood pressure
• Calibration, maintenance, and use of blood
  pressure measuring devises

• Patient evaluation
• Identifiable causes of hypertension
• Genetics of hypertension
• Treatment
• Special situation in hypertension management
• Drugs and other agents affecting blood pressure
• Improving hypertension control

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Introduction

• Worldwide prevalence estimates for hypertension
  may be as much as 1 billion individuals, and
  approximately 7.1 million deaths per year may be
  attributable to hypertension
• The World Health Organization reports that
  suboptimal BP (gt115 mmHg SBP) is responsible for
  62 percent of cerebrovascular disease and 49
  percent of ischemic heart disease

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Introduction
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Introduction
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Introduction
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Introduction
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Lifetime risk of hypertension
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Lifetime risk of hypertension

• Remaining lifetime risks of hypertension
• women 8690
• men 8183
• 4-year rates of progression to hypertension
• 65 years and older with BP in the 130139/8589
  mmHg range 50
• 65 years and older with BP between 120129/8084
  mmHg 26

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Blood pressure and cardiovascular risk

• The increased risks are present in individuals
  ranging from 40 to 89 years of age.
• For every 20 mmHg systolic or 10 mmHg diastolic
  increase in BP, there is a doubling of mortality
  from both IHD and stroke

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Blood pressure and cardiovascular risk
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Basis for reclassification of blood pressure
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Classification of blood pressure

• Prehypertension
• is not a disease category
• identify individuals at high risk of developing
  hypertension
• encouraged to intervene and prevent or delay the
  disease from developing.
• not candidates for drug therapy
• advised to practice lifestyle modification in
  order to reduce their risk of developing
  hypertension in the future
• Prehypertension diabetes or kidney disease
• should be considered candidates for appropriate
  drug therapy if a trial of lifestyle modification
  fails to reduce their BP to 130/80 mmHg or less.
• All people with hypertension (stages 1 and 2) be
  treated

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Importance of systolic blood pressure

• The rise in SBP continues throughout life
• DBP rises until approximately age 50, tends to
  level off over the next decade, and may remain
  the same or fall later in life.
• DBP is a more potent cardiovascular risk factor
  than SBP until age 50 thereafter, SBP is more
  important.

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Importance of systolic blood pressure
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Calibration, maintenance, and use of blood
pressure measuring devise

• Persons should be seated quietly for at least 5
  minutes
• in a chair (rather than on an exam table),
• with feet on the floor
• arm supported at heart level
• Caffeine, exercise, and smoking should be avoided
  for at least 30 minutes prior to measurement
• An appropriately sized cuff (cuff bladder
  encircling at least 80 percent of the arm) should
  be used to ensure accuracy

• At least two measurements should be made and the
  average recorded.
• The cuff deflation rate for auscultatory readings
  should be 2 mmHg per second.
• SBP is the point at which the first of two or
  more Korotkoff sounds is heard (onset of phase 1)
• The disappearance of Korotkoff sound (onset of
  phase 5) is used to define DBP.

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Patient Evaluation

• To assess lifestyle and identify other
  cardiovascular risk factors or concomitant
  disorders that may affect prognosis and guide
  treatment
• To reveal identifiable causes of high BP
• To assess the presence or absence of target organ
  damage and CVD.

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Patient Evaluation
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Treatment

• In the majority of patients, reducing SBP has
  been considerably more difficult than lowering
  DBP.
• The majority will require two or more
  antihypertensive drugs.
• The causes of BP control failure
• failure to prescribe lifestyle modifications,
• inadequate antihypertensive drug doses,
• or inappropriate drug combination

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Treatment

• Goal of therapy
• Reaching the DBP goal once the SBP goal is
  achieved
• the primary focus should be on attaining the SBP
  goal.
• Treating SBP and DBP to targets that are lt140/90
  mmHg is associated with a decrease in CVD
  complications.
• In patients with hypertension and diabetes or
  renal disease, the BP goal is lt130/80 mmHg

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Treatment
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Treatment
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Drugs and other agents affecting blood pressure
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New agents for Dyslipidemia
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Ezetimibe

• 2-azetidinones (2-aze)
• Interfere with cholesterol absorption (similar to
  bile acid sequestrant)
• provide enhanced cholesterol lowering when used
  concomitantly with statins
• do not interfere with the absorption of
  concurrently administered medications

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Ezetimibe

• Mechanism of action
• Absorption of cholesterol
• Ingestion and delivery into the intestinal lumen,
• Dietary cholesterol is absorbed predominantly in
  the duodenum and jejunum, in an unesterified form
• Upon entry into the intestines, cholesterol is
  esterified by acyl-CoAcholesterol
  acyltransferase (ACAT)
• ACATis incorporated into chylomicrons conjointly
  with triglycerides.
• Chylomicrons are then delivered to the
  circulation through the lymphatic system.

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Two Sources of Cholesterol
Dietary cholesterol(300700 mg/day)
Fecal bile acids and neutral sterols
Intestine
Biliarycholesterol(1000 mg/day)
700 mg/day
Liver
Synthesis(800 mg/day)
Extrahepatictissues
Adapted from Champe PC, Harvey RA. Biochemistry.
2nd ed. Philadelphia Lippincott Raven, 1994
Glew RH. In Textbook of Biochemistry with
Clinical Correlations. 5th ed. New York
Wiley-Liss, 2002728-777 Ginsberg HN, Goldberg
IJ. In Harrisons Principles of Internal
Medicine. 14th ed. New York McGraw-Hill,
19982138-2149 Shepherd J Eur Heart J Suppl
20013(suppl E)E2-E5 Hopfer U. In Textbook of
Biochemistry with Clinical Correlations. 5th ed.
New York Wiley-Liss, 20021082-1150.
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Cholesterol Synthesis
Acetyl-CoA
Acetoacetyl-CoA
HMG-CoA
HMG-CoA reductase
Hepatocyte
Mevalonate
Cholesterol
Adapted from Dietschy JM Am J Clin Nutr
1997651581S-1589S.
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Cholesterol Absorption
ABCA1
ABCA1adenosine triphosphatebinding cassette
protein ACATacyl-coenzyme Acholesterol
acyltransferase CMchylomicron Adapted from
Champe PC, Harvey RA. Lippincotts Illustrated
Reviews Biochemistry. 2nd ed. Philadelphia
Lippincott-Raven, 1994.
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Ezetimibe

• Mechanism of action
• Cholesterol transit across intestinal cellular
  walls uses a specific protein-mediated
  transport system.
• 2-aze bind to a protein on or within the brush
  border membrane of intestinal cells.
• 2-aze relatively specific for inhibits
  cholesterol absorption by inhibiting the
  transport system.
• Ezetimibe had no impact on the absorption of
• triglycerides,
• ethinyl estradiol,
• progesterone,
• fatsoluble vitamins (e.g., vitamin A, vitamin D,
  tocopherol, or carotenoid)

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Ezetimibe

• Pharmacokinetics
• Ezetimibe is readily taken up by intestinal cells
• primarily glucuronidated within the intestinal
  wall to the pharmacologically active ezetimibe
  glucuronide (SCH 60663)
• SCH 60663
• is delivered to the liver by the portal system
• secreted back into the intestinal lumen via the
  biliary system
• binds to the intestinal wall.
• minimal systemic distribution of unconjugated
  ezetimibe or SCH 60663 occurs.
• more potent in inhibiting cholesterol absorption
  than ezetimibe

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Ezetimibe

• Pharmacokinetics
• Enterohepatic recirculation
• SCH 60663 being deconjugated back to ezetimibe,
  which is then reabsorbed in the ileum.
• This process appears to recur every 4 hours for
  several cycles and corresponds with meals.
• Due to enterohepatic recirculation, it is
  difficult to truly determine an elimination
  half-life.
• The effective half-life of ezetimibe has been
  estimated to be 2830 hours
• Ezetimibe and its conjugate are gt90 bound to
  plasma proteins.
• 80 of an ezetimibe dose is eliminated fecally,
  with 10 eliminated renally.

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Ezetimibe

• Adverse drug reactions
• occur slightly more frequentlywith ezetimibe than
  with placebo
• Chest pain,
• arthralgia,
• diarrhea,
• dizziness,
• headache
• Liver or skeletal muscle dysfunction has not been
  associated with ezetimibe when used alone or in
  combination with other agents.

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Ezetimibe

• Drug interactions
• no impact on CYP1A2, 2C8/9, 2D6, 3A4
• Fenofibrate and gemfibrozil have increased total
  ezetimibe concentrations by 50
• Cholystyramine considerably decreased total
  ezetimibe concentrations
• Antacid ezetimibe the AUC for total ezetimibe
  did not differ, although the rate of absorption
  was reduced

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Ezetimibe

• Dosage and administration
• 10-mg tablet given once daily with or without
  food
• ingested at least 2 hours before or 4 hours after
  a BAS
• Peak LDL-C lowering is generally achieved after 2
  weeks of therapy.
• contraindicated in patients with active liver
  disease or continuously elevated liver enzymes
• Liver function monitoring is not required when
  zetimibe is used alone
• No dosage adjustment is recommended by the
  manufacturer for elderly patients or patients
  with renal insufficiency or mild liver
  insufficiency.

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Ezetimibe

• Role of therapy
• Ezetimibe significantly lowers LDL-C
  concentrations (gt 20) and modestly increases
  HDL-C and lowers triglyceride concentrations.
• most likely will be in combination with a statin
  in patients who are unable to achieve target
  LDL-C concentrations using a statin alone.
• Homozygous form of familial hypercholesterolemia
• Elevated sitosterol first-line treatment and
  monotherapy

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Bile acid sequestrants
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Rosuvastatin

• A hydroxymethylglutaryl coenzyme A (HMG-CoA)
  reductase inhibitors
• Competitively inhibition
• the rate-limiting enzyme necessary for the
  biosynthesis of cholesterol
• are structural analogues of the half-reduced
  intermediate of HMG-CoA

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Rosuvastatin
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Rosuvastatin
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Rosuvastatin

• Hepatocyte selectivity
• Rosuvastatin and pravastatin are selective for
  hepatocytes in vivo
• This is consistent with the relatively
  hydrophilic properties of both drugs
• Drug interactions
• Cyclosporine and rosuvastatin concomitantly
  should be initiated on rosuvastatin 5 mg once
  daily.
• Warfarin and rosuvastatin warfarin therapy
  should be monitored for international normalized
  ratio changes

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Rosuvastatin

• Approximate equivalent doses for rosuvastatin
  appear to be
• one-half the atorvastatin dose
• one-fourth the simvastatin dose
• one-eighth the pravastatin dose (eg, substitute
  rosuvastatin 5 mg for atorvastatin 10 mg,
  simvastatin 20 mg, and pravastatin 40 mg).

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Third Report of the Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel
III)

• Circulation. 2002 1063143-421

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Revision and Addition of ATP III

• Designation of a CHD risk equivalent category
  identifying patients who require aggressive lipid
  management
• Recommendation of Framingham-based CHD risk
  assessment in patients with multiple risk factors
• Revised target levels for several of the lipids
  and lipoproteins
• Criteria for the identification of patients with
  the metabolic syndrome

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CHD risk equivalent
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Target levels for several of the lipids and
lipoproteins
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Therapeutic Goals
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Detection of metabolic syndrome
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Initiation of Drug Therapy
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New Agents for Asthma/COPD
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Formoterol

• A ß2-selective adrenoceptor agonist
• Has a rapid onset of action and maintains
• a bronchodilatory effect for up to 12 hours.
• Has minimal stimulating effects on
  ß1-adrenoceptors and virtually no effect on
  a-adrenoceptors

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Formoterol

• Dose and administration
• The current recommended dosage of inhaled
  formoterol for adults and children 6 years and
  older
• 6mg twice daily via Turbuhaler, or
• 12mg (1 puff) twice daily via Aerolizer or
• other dry powder devices or MDI.
• If the recommended dosage does not sufficiently
  control symptoms, it may be increased to 24mg
  twice daily and subsequently be titrated
  according to effect.

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Formoterol

• Dosage and administration
• Formoterol should be administered in conjunction
  with regular doses of inhaled or oral
  corticosteroids.
• The current recommendations for the use of
  formoterol are as an alternative to increased
  dosages of inhaled corticosteroids in patients
  who remain symptomatic while receiving low to
  moderate doses of inhaled corticosteroids.
• Therapeutic role
• is a long-acting b2-agonist currently recommended
  for maintenance therapy
• should not be used to treat acute exacerbations
  of asthma.

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Formoterol/Budesonide

• Fixed-combination inhalers, such as
  budesonide/formoterol formulation, are
  recommended as a convenient way of administering
  an inhaled corticosteroid plus a long-acting
  ß2-agonist
• Most of the antiinflammatory effect can be
  achieved at lower dosage of steroids
• The complementary bronchodilator effects of
  additional long-acting ß2-agonists and the
  possibility of positive interactions between the
  two classes may make it possible to reduce the
  dose of inhaled corticosteroids while maintaining
  the same degree of asthma control

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Guideline on the Diagnosis and Management of
Asthma

• April 2004

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Assess Asthma Severity

• Step 1 Mild Intermittent
• symptoms lt 2 times a week
• asymptomatic and normal PEF between exacerbations
• exacerbations are brief (few hours to a few days)
• nighttime symptoms lt 2 times a month
• FEV1 or PEF gt 80 percent predicted and PEF
  variability lt 20 percent

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Assess Asthma Severity

• Step 2 Mild Persistent
• symptoms gt 2 times a week but lt 1 time a day
• exacerbations may affect activity
• nighttime symptoms gt 2 times a month
• FEV1 or PEF gt 80 percent predicted and PEF
  variability 20-30 percent

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Assess Asthma Severity

• Step 3 Moderate Persistent
• daily symptoms
• daily use of inhaled short-acting beta2-agonists
• exacerbations affect activity
• exacerbations gt 2 times a week may last days
• nighttime symptoms lt 1 time a week
• FEV1 or PEF gt 60 percent - lt 80 percent predicted
• PEF variability gt 30 percent

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Assess Asthma Severity

• Step 4 Severe Persistent
• continual symptoms
• limited physical activity
• frequent exacerbations
• frequent nighttime symptoms
• FEV1 or PEF lt 60 percent and PEF variability gt 30
  percent

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Step Care of Pharmacologic Treatment
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Step Care of Pharmacologic Treatment