presented by: manar lashkar samah al-shehri pharm.d candidates

Manar & Samah1

Supervised by:

Dr. Seema

King Faisal Specialist Hospital and Research Center

(2007-1428)

Presented by: Manar LashkarSamah Al-shehriPharm.D candidates

Manar & Samah 2

Manar & Samah 3

Outline• Hypertension• JNC VII Guidelines• Resistant hypertension• Pheochromocytoma• Case Scenario• Points of Discussion

Manar & Samah 4

• Hypertension affects more than 20% of the adult Saudi population with expected increasing prevalence

• It is an important modifiable risk factor for cardiovascular diseases

• Despite overwhelming evidence that lowering BP reduces morbidity and mortality, its management remains frequently sub-optimal

Manar & Samah 5

Hypertension

• It is defined as persistent elevation of systolic blood pressure SBP ≥ 140 mm Hg and/or diastolic blood pressure DBP ≥ 90 mm Hg in adults not on anti-hypertensive medications

• It can be classified as either essential (primary) or secondary Essential hypertension indicates that no specific medical cause

can be found to explain a patient's condition

Secondary hypertension indicates that the high blood pressure is a result of (i.e. secondary to) another condition

Manar & Samah 9

Identifiable Causes of Hypertension

• Chronic kidney disease• Coarctation of the aorta• Cushing’s syndrome and other glucocorticoid

excess states including chronic steroid therapy• Drug induced or drug related• Obstructive uropathy• Pheochromocytoma• Primary aldosteronism and other mineralocorticoid

excess states• Renovascular hypertension• Sleep apnea• Thyroid or parathyroid disease

Manar & Samah 10

Blood Pressure Classification

SBP mm Hg DBP mm HG

Normal < 120 and < 80

Prehypertension 120-139 or 80-89

Stage 1 Hypertension

140-159 or 90-99

Stage 2 Hypertension

> 160 or > 100

Classification of Blood Pressure for Adults

Manar & Samah 11

Resistant hypertension is defined as the failure to achieve goal BP in patients who are adhering to full doses of an appropriate three-drug regimen that includes a diuretic

Resistant Hypertension

Manar & Samah 12

■ Nonadherence■ Inadequate doses■ Inappropriate combinations■ Nonsteroidal anti-inflammatory drugs; cyclooxygenase 2 inhibitors■ Cocaine, amphetamines, other illicit drugs■ Sympathomimetics (decongestants, anorectics)■ Oral contraceptive hormones■ Adrenal steroid hormones■ Cyclosporine and tacrolimus■ Erythropoietin■ Licorice (including some chewing tobacco)■ Selected over-the-counter dietary supplements and medicines(e.g., ephedra, bitter orange)

Causes of Resistant Hypertension

■ Excess sodium intake■ Volume retention from kidney disease■ Inadequate diuretic therapy

Volume overload

Drug-induced or other causes

■ Obesity■ Excess alcohol intake

Associated conditions

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Manar & Samah 16

Class Drug Usual Dose Range (mg/d)

Daily Frequency

Thiazide Diuretics HydrochlorothiazideIndapamideMetolazone

12.5-501.25-2.52.5-5

ODODOD

Loop Diuretics Furosemide 20-80 BID

Potassium Sparing Diuretics

AmilorideTriamterene

5-1050-100

OD/BIDOD/ BID

Aldosterone receptor blocker

Spironolactone 25-50 OD/BID

Adverse Effects Special Precautions

hyperurecimia, glucose intolerance, dyslipidemia, sexual dysfunction, dehydration, increase Ca, decrease (K, Na, Mg), skin rash and photosensitivity

Gout, renal failure, digoxin, lithium


Loop diuretics Similar to thiazide diuretics except hypocalcemia

Effect in patients with renal insufficiency

Class Adverse Effects Special Precautions

Potassium Sparing Diuretics

Triamterene urinary sediment, nephrolithiasis

Renal dysfunction, Diabetes, ACEI

Aldosterone receptor blocker

Gynecomastia, impotence, hirsutism, menstrual irregularities, GI symptoms.

Diuretics

Manar & Samah 17


Daily Frequency

b-Blockers AtenololBisoprololMetoprololPropranolol

25-1002.5-1050/10040/160

ODODOD/BIDBID

b-Blockers with ISA

Acebutolol 200-800 BID

Combined a/b Blocker

carvedilolLabetalol

12.5-50200-800

BIDBID

a1 Blocker DoxazocinPrazocin

1-162-20

ODBID/TID

Central a2 agonist ClonidineMethyldopaReserpine

0.1-1.8250-10000.05-0.25

BIDBIDOD


Fatigue, insomnia, nightmare, depression, sexual dysfunction, dyslipidemia, rash, withdrawal rebound coronary heart disease, bradycardia, GI upset, mask symptoms of hyperglycemia

Asthma, COPD, Decompensated CHF, heart block, DM, peripheral vascular disease.

Less bradycardia and dyslipidemia, drug-induced Lupus Erythematosus

Orthostatic hypotension, hepatotoxiciy No dyslipidemia


a1-Blocker Syncope after first dose or dose increase, orthostatic hypotension, headache, dizziness, drowsiness, tachycardia, sodium and fluid retention.

Advanced age, first dose

Central a2

agonist

Sedation, dry mouth, sexual dysfunction, withdrawal rebound hypertension, impaired mental concentrationMethyldopa (hepatitis, Coombs-positive hemolytic anemia, colitis, drug-induced lupus erythematosus)

Depression, taper dosage when discontinue to avoid rebound.

Adrenergic Blockers

Manar & Samah 18


Daily Frequency

Angiotensin Converting Enzyme Inhibitor

CaptoprilEnalapril

25-1002.5-40

BIDOD/BID

Angiotensin II Antagonist

CandesartanIrbesartanLosartanValsartan

8-32150-30025-10080-320

ODODOD/BIDOD/BID

Calcium Channel Blocker

AmlodipineNifedipine LAVerapamil LADiltiazem LA

2.5-1030-60120-360120-540

ODODOD/BIDOD

Direct Vasodilator Hydralazine 25-100 BID


Hyperkalemia, cough, hypotension, angioedema, loss of taste, renal failure, neutropenia, cholestasis, rash, blood dyscrasias.

Renal failure, pregnancy, renal artery stenosis

Similar to ACEI but do not cause cough


Calcium Channel Blocker

Headache, flushing, hypotension, dizziness, palpitation, rashDihydropyridines (edema, tachycardia)Diltiazem (Lupus-like rash)Verapamil (Constipitation, bradycardia, AV block)

Congestive heart failure, heart block

Direct Vasodilator

Headache, dizzines, sodium and fluid retention, positive antinuclear antibody, lupus-like syndrome, hepatitis, nasal congestion, GI disturbance.

ACE-I, ARBs, CCB, and Direct Vasodilator

Manar & Samah 19

After age 50, high systolic blood pressure (> 140 mm Hg) is much more important than high diastolic pressure as a risk

factor for cardiovascular events

People who are normotensive at age 55 still have a 90% lifetime risk for developing hypertension.

People with a systolic blood pressure of 120 to 139 mm Hg or a diastolic pressure of 80 to 89 mm Hg should be considered

prehypertensive and should undertake health promoting lifestyle modifications to prevent cardiovascular disease.

Thiazide-type diuretics should be used to treat most patients with uncomplicated hypertension, either alone or combined

with drugs from other classes, but certain high risk conditions constitute compelling indications for the initial use of other

types of antihypertensive drugs

Most patients with hypertension need two or more antihypertensive medications to achieve their goal pressure

(< 140/90 mm Hg or < 130/80 mm Hg for patients with diabetes or chronic kidney disease).

If blood pressure is more than 20/10 mm Hg above goal, one should consider starting therapy with two agents, one of which

usually should be a thiazide-type diuretic

Manar & Samah 20

Pheochrmocytoma

• Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells (medulla)

• Because of excessive catecholamine secretion, pheochromocytomas may precipitate life-threatening hypertension or cardiac arrhythmias

Manar & Samah 22

Symptoms and Signs

Symptoms• Headache • Diaphoresis • Palpitations • Tremor • Nausea • Weakness • Anxiety

Clinical signs• Hypertension (50% paroxysmal)

• Postural hypotension• Hypertensive

retinopathy • Pallor • Fever • Tachyarrhythmias • Pulmonary edema

Manar & Samah 24

Risk Factors

• Precipitants of a hypertensive crisis – Anesthesia induction – Opiates – Dopamine antagonists – Cold medications – Radiographic contrast media – Drugs that inhibit catecholamine reuptake, such

as tricyclic antidepressants and cocaine – Childbirth

Manar & Samah 28

Manar & Samah 29

Interventions:CAD CABG (2002, KFMH)PCI LCX (5/2006)PCI RCA (12/2006)

Labs: (7/2007)Ejection Fraction= 40-45%Negative Thallium

A 75-year-old female with a history of:

Past Medical History:HypertensionLeft Bundle Branch BlockDiabetes MellitusChronic renal impairment (Serum Cr = 127umol/L)Bronchial AsthmaOsteoporosis

Social History:Quit smoking 3 years ago

Manar & Samah 30

Past Medication History

• Aspirin 81 mg PO OD• Clopidogrel 75 mg PO OD• Carvedilol 12.5 mg PO BID• Atorvastatin 40 mg PO OD• Amlodipine 10 mg PO OD• Irbesartan 300 mg PO OD• Furosemide 60 mg PO BID• Isosorbide dinitrate retard 40 mg PO OD

Manar & Samah 31

On 10/12/2007

• Came to arrhythmia clinic complaining of recurrence syncope and blood pressure of 206/100 mm Hg

• Admitted to N2 (cardiology ward)

Manar & Samah 32

During whole admission period she was on

• Aspirin 81 mg PO OD• Gabapentin 400 mg PO BID• Clopidogrel 75 mg PO OD• Atorvastatin 40 mg PO OD• Insulin regular SC (Sliding Scale) Q6h <8.3 ------------- none 8.4-11.1 --------2 units 11.2-13.9-------4 units 14-16.7----------6 units 16.8-19.4-------8 units 19.5-22.2------10 units >22.3-----------notify MD and do STAT blood sugar, urine ketone

Manar & Samah 33

11\12 18\1217\1216\1215\1214\1213\1212\12

Hyp

ertensio

n A

sthm

aO

thers

11\12 18\1217\1216\1215\1214\1213\1212\12

11\12 18\1217\1216\1215\1214\1213\1212\12

Surgery for single chamber pacemaker

implantation

Recurrence Syncope

She started to have tremor

Manar & Samah 35

Hyp

ertensio

nC

OP

D/ A

sthma

Others

11\12 18\1217\1216\1215\1214\1213\1212\12

11\12 18\1217\1216\1215\1214\1213\1212\12

Irbesartan

300 mg PO OD

Isosorbide dinitrate retard

20 mg PO BID

Amlodipine

PO OD

carvedilol

12.5 mg PO BID

Furosemide

40 mg IV

40 mg PO OD

10 mg 5 mg

11\12 18\1217\1216\1215\1214\1213\1212\12

010

203040

5060

708090

100110120

130140150

160170

180190200

210220

11/12/2007

11/12/2007

11/12/2007

11/12/2007

12/12/2007

12/12/2007

13/12/2007

13/12/2007

13/12/2007

14/12/2007

14/12/2007

14/12/2007

15/12/2007

15/12/2007

15/12/2007

16/12/2007

16/12/2007

16/12/2007

17/12/2007

17/12/2007

17/12/2007

18/12/2007

18/12/2007

18/12/2007

11\12 18\1217\1216\1215\1214\1213\1212\12

SrCr160 umol/L

Manar & Samah 36

11\12 18\1217\1216\1215\1214\1213\1212\12

Hyp

ertensio

nA

sthm

aO

thers

11\12 18\1217\1216\1215\1214\1213\1212\12

11\12 18\1217\1216\1215\1214\1213\1212\12

Irbesartan

300 mg PO OD


20 mg PO BID

Amlodipine

PO OD

carvedilol

12.5 mg PO BID

Furosemide

40 mg IV

40 mg PO OD

10 mg 5 mg

Fluticasone/salmeterol

250/25 mcg/ puff BID

Budesonide nebulizer

500 mcg TID

Ipratropium nebulizer

500 mcg TID

Asthma

Attack

Manar & Samah 38

Irbesartan

300 mg PO OD


PO BID

Amlodipine

10 mg PO OD

Nifedipine LA

60 mg PO STAT

Captopril

6.25 mg PO TID

carvedilol

12.5 mg PO BID

Metoprolol

12.5 mg PO BID

Clonidine

100 mcg PO OD

Furosemide

IV BID

20 mg PO

40 mg PO

Hyp

ertensio

n19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

20 mg 40 mg

40 mg 60 mg 40 mg

0102030405060708090

100110120130140150160170180190200210220230240

19/12/2007

20/12/2007

21/12/2007

22/12/2007

23/12/2007

24/12/2007

25/12/2007

26/12/2007

27/12/2007

28/12/2007

29/12/2007

30/12/2007

31/12/2007

01/01/2008

01/02/2008

01/03/2008

01/04/2008

01/05/2008

01/12/2008

13/1/2008 Series1

Series2

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

SrCr107 umol/L

?

Manar & Samah 39

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

Methylprednisolone

60 mg IV OD

Prednisolone

PO OD

Magnesium Sulphate

2 g IV

Different inh/neb

60 mg 50 mg 15 mg30 mg 20 mg 10 mg 5 mg40 mg

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

Ca polystyrene Sulphonate

30 g PO OD

Heparin Sodium

5000 U S.C BID

Asth

ma

Oth

ersH

yperten

sion

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

K 5.3 mmol/L K 5.4 mmol/LK 5.5 mmol/L

CO

PD

Manar & Samah 40

Patient was distress, tachypnic, wheezing, complaining of shortness of breath, orthopnea, bilateral chest crepitation

Manar & Samah 41

Transferred to ICU

Manar & Samah 42

Hyp

ertensio

nC

OP

D/ A

sthm

aO

thers

5\1 10\19\18\17\16\1

5\1 10\19\18\17\16\1

5\1 10\19\18\17\16\1

Manar & Samah 43

Hyp

ertensio

n

Irbesartan

300 mg PO OD

Amlodipine

10 mg PO OD

Nitroglycerin

5 mg SL stat

200 mcg/ml INF

Clonidine

100 mcg PO OD

Enalapril

5 mg PO OD

Furosemide

IV BID

5\1 10\19\18\17\16\1

60 mg 40 mg 40 mg 40 mg80 mg80 mg

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

5\1 10\19\18\17\16\1

Manar & Samah 44

Oth

ers

5\1 10\19\18\17\16\1

5\1 10\19\18\17\16\1

Hydrocortisone

IV stat

IV TID

Different Neb/Inh

Aminophylline

IV 250 mg stat

80 mg 40 mg

20 mEq 40 mEq

Piperacillin/Tazobactam

2.25 mg IV Q6h

Potassium Chloride

IV over 2h

40 mEq PO

Heparin (PROTECT study)

5\1 10\19\18\17\16\1

Hyp

ertensio

nIrbesartan

300 mg PO OD

Amlodipine

10 mg PO OD

Nitroglycerin

5 mg SL stat

200 mcg/ml INF

Clonidine

100 mcg PO OD

Enalapril

5 mg PO OD

Furosemide

IV BID60 mg 40 mg 40 mg 40 mg80 mg80 mg

K 3.5 mmol/L K 2.9 mmol/L

Hospital Acquired Pneumonia

CO

PD

Manar & Samah 45

Returned to Cardiology Ward

Manar & Samah 46

11/1 12/1 14/1 15/1 16/1 17/1 18/1 19/1 20/1 21/1 22/113/1

Irbesartan

300 mg PO OD

Amlodipine

10 mg PO OD

Nifedipine LA

60 mg PO OD

Nitroglycerin

200 mcg/ml INF

Isosorbide dinitrate

40 mg PO BID

Spironolactone

25 mg PO OD

Hydralazine

25 mg PO BID

Enalapril

PO

Furosemide

40 mg IV BID

40 mg PO OD

10 mg BID10 mg QD

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

Series1

Series2

Hyp

ertensio

n

11/1 12/1 14/1 15/1 16/1 17/1 18/1 19/1 20/1 21/1 22/113/1

Manar & Samah 47

Hyp

ertensio

nC

OP

DO

thers

11/1 12/1 14/1 15/1 16/1 17/1 18/1 19/1 20/1 21/1 22/113/1

PrednisolonePO QD

Different Neb/Inh

20 mg 10mg 5 mg

Heparin Sodium 5000 U S.C BIDPotassium Chloride40 mEq IV40 mEa PO OD

K 2.8 mmol/L

K 3.2 mmol/L

11/1 12/1 14/1 15/1 16/1 17/1 18/1 19/1 20/1 21/1 22/113/1

10 mg BID10 mg QD

Irbesartan

300 mg PO OD

Isosorbide dinitrate

40 mg PO BID

Amlodipine

10 mg PO OD

Nifedipine LA

60 mg PO OD

Spironolactone

25 mg PO OD

Hydralazine

25 mg PO BID

Enalapril

PO

Nitroglycerin

200 mcg/ml INF

Furosemide

40 mg IV BID

40 mg PO OD

11/1 12/1 14/1 15/1 16/1 17/1 18/1 19/1 20/1 21/1 22/113/1

Hyp

ertensio

n

Manar & Samah 49

Hypertension/CV ProblemsCOPD

Daibetes/ComplicationsOsteoporosis

was on

• Insulin NPH SC 32 Units BID• Gabapentin 400 mg PO BID

Same Medicationswas on

Was not managed before

• Alfacalcidol 0.5 mcg PO OD• Calcium carbonate 500 mg

PO BID

Problems List/Medications

carvedilol 12.5 mg PO BIDSpironolactone 25 mg PO ODIrbesartan 300 mg PO ODFurosemide 40 mg PO BIDNifedipine LA 60 mg PO BIDEnalapril 10 mg PO BIDHydralazine 25 mg PO BIDIsosorbide dinitrate retard 20 mg PO BIDAspirin 81 mg PO ODClopidogrel 75 mg PO ODAtorvastatin 40 mg PO OD

carvedilol 12.5 mg PO BID

Irbesartan 300 mg PO ODFurosemide 60 mg PO BID

Isosorbide dinitrate retard 40 mg PO ODAspirin 81 mg PO ODClopidogrel 75 mg PO ODAtorvastatin 40 mg PO ODAmlodipine 10 mg PO OD

Was not managed before

• Prednisolone 5 mg PO OD (for 15 days)

• Fluticasone/ Salmetrol inhaler 2 puffs TID

• Albuterol 2 puffs inhaler PRN

DischargeMedications

Manar & Samah 50

Points of Discussion

Manar & Samah 60

I) Prednisolone Side Effect and Tapering

Manar & Samah 61

Corticosteroids Side Effects

Prolonged therapy can lead to suppression of pituitary-adrenal function

Too rapid withdrawal of long-term therapy can cause acute adrenal insufficiency (e.g. fever, myalgia, arthralgia and malaise)

• Adverse reactions:Dose and duration related side effects include fluid and electrolyte disturbance (e.g. hypokalemia with possible edema and hypertension), hyperglycemia, peptic ulcer disease, osteoporosis, euphoria, psychosis, myopathy, and infections

In our case the patient suffered from:

• Myopathy

• Uncontrolled hypertension

• Hypokalemia

• Hospital acquired pneumonia

• The patient is predisposed to osteoporosis

Manar & Samah 62

Corticosteroids Tapering Off

There are many regimens for tapering off corticosteroids.

Example of prednisone tapering schedule:Dosage (mg) Duration (wks)

20 2

17.5 3

15 4

15 alternating with 12.5

2-4

15 alternating with 10 2-4

15 alternating with 7.5 2-4

15 alternating with 5 2-4

15 alternating with 2.5 2-4

20 alternating with 0 4

17.5 alternating with 0 4

15 alternating with 0 4

However, corticosteroids can be rapidly tapered and

discontinued abruptly if used for less than 2 to 3 weeks

Manar & Samah 63

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

Methylprednisolone

60 mg IV OD

Prednisolone

PO OD

Magnesium Sulphate

2 g IV

Different inh/neb

60 mg 50 mg 15 mg30 mg 20 mg 10 mg 5 mg40 mg

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

Ca polystyrene Sulphonate

30 g PO OD

Heparin Sodium

5000 U S.C BID

Guaifenesin/ Dextromethorphan

10 ml PO BID

Asth

ma

Oth

ersH

yperten

sion

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

myopathy

CO

PD

This is not a prednisolone tapering off. The goal of decreasing the dose was to seek for the lowest effective and tolerated dose that can manage her COPD with minimum myopathy and fluid retention

Manar & Samah 64

• II) b-Blocker Withdrawal

Manar & Samah 65

b-Blocker Withdrawal

Withdrawing b-blockers may produce b-adrenergic supersensitivity. Both abrupt cessation and gradual withdrawal over 4 to 8 days have caused overshoot hypertension and cardiovascular complications within within 48 to 72 hours after the last b-blocker dose

To prevent b-adrenergic supersensitivity, the b-blocker dosage should be reduced over 7 to 10 days to the equivalent of 30 mg/day of propranolol and then maintained at this low dosage

for 2 additional weeks

b-blocker Withdrawal in patient who are free of CHD resulted in fourfold increase in onset of CHD

Manar & Samah 66

Irbesartan

300 mg PO OD


PO BID

Amlodipine

10 mg PO OD

Nifedipine LA

60 mg PO STAT

Captopril

6.25 mg PO TID

carvedilol

12.5 mg PO BID

Metoprolol

12.5 mg PO BID

Clonidine

100 mcg PO OD

Furosemide

IV BID

20 mg PO

40 mg PO

Hyp

ertensio

n19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

20 mg 40 mg

40 mg 60 mg 40 mg

0102030405060708090

100110120130140150160170180190200210220230240

19/12/2007

20/12/2007

21/12/2007

22/12/2007

23/12/2007

24/12/2007

25/12/2007

26/12/2007

27/12/2007

28/12/2007

29/12/2007

30/12/2007

31/12/2007

01/01/2008

01/02/2008

01/03/2008

01/04/2008

01/05/2008

01/12/2008

13/1/2008 Series1

Series2

19/12 20/12 31/1222/12 23/12 24/12 25/12 26/12 27/12 28/12 29/12 30/1221/12 1/1 4/12/1 3/1

Titration of the cavedilol 12.5 mg to metoprolol 12.5 mg Then D/C b-blocker after 8 days

Manar & Samah 67

Manar & Samah 68

References• Chobanian AV, Bakris GL, Black HR, et al and the National High Blood Pressure Education

Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7 report. JAMA 2003; 289:2560–2572.

• Vidit D, Borazanian R. Treat high blood pressure sooner: Tougher, simpler JNC 7 guidelines. Cleveland Clinic Journal of Medicine 2003; 70(8):721-728

• Saudi Hypertension Management Society. Saudi hypertension guidelines. 2007; 1-46

• Helms R, Quan D, Herfindal E eds. Textbook of therapeutics. Drug and disease management. Eighth Edition. Philadelphia, PA. Lippincott Williams & Wilkins; 2006: 451-471

• Herfindal E and Gourley D. Textbook of therapeutics. Drug and disease management. Seventh Edition. Philadelphia, PA. Lippincott Williams & Wilkins; 2000: 795-823

• http://www.emedicine.com/MED/topic1106.htm

presented by: manar lashkar samah al-shehri pharm.d candidates

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