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PHERIPHERAL ARTERY DISEASE
IN DIABETES
DR. S.K.SHARMA
CONSULTANT ENDOCRINOLOGIST
JAIPUR.
ADA Guidelines for PAD care inADA Guidelines for PAD care in
DiabeticsDiabetics
 29% prevalence of PAD in diabetics over2...
PAD underdiagnosed inPAD underdiagnosed in
DiabeticsDiabetics
 Of all patients with PAD, half areOf all patients with PAD...
Goals Of TreatmentGoals Of Treatment
 Symptom controlSymptom control
 Prevention of Limb lossPrevention of Limb loss
 R...
Screening & DiagnosisScreening & Diagnosis
 ABI is recommended in all diabetic patientsABI is recommended in all diabetic...
Screening & Diagnosis(cont.)Screening & Diagnosis(cont.)
 Functional testing with a graded treadmill isFunctional testing...
Treatment of Asymtomatic PADTreatment of Asymtomatic PAD
in Diabeticsin Diabetics
 Smoking cessationSmoking cessation
 P...
Treatment of Symptomatic PADTreatment of Symptomatic PAD
in Diabeticsin Diabetics
 Customized footwear to reduce pressure...
Treatment of Symptomatic PADTreatment of Symptomatic PAD
in Diabetics(cont.)in Diabetics(cont.)
 For all infections, inci...
SUMMARYSUMMARY
 Screening with ABI should be conducted in allScreening with ABI should be conducted in all
diabetic patie...
PAD Atherosclerotic occlusive disease of the
lower extremities
Epidemiology
USA – 12 million people suffering from
PAD
20%...
PAD IN DIABETES
In diabetes risk of PAD
Age
Duration of diabetes
Pheripheral Neuropathy
Ethnic group– African, American &
...
PREVALENCE OF PAD IN INDIAPREVALENCE OF PAD IN INDIA
 CUPS; n=631CUPS; n=631
 Overall prevalence of PAD=3.2%Overall prev...
PREVALENCE OF PAD IN INDIAPREVALENCE OF PAD IN INDIA
(contd)(contd)
Age groupAge group Normal glucoseNormal glucose Glucos...
In diabetes - Femoral,popliteal & tibial vessel (below the
knee)
In smokers - More proximal disease Aorta-ilio femoral ves...
IMPORTANCE OF DIAGNOSIS OF PAD IN
DIABETES
 Identify patient with high risk of MI,Stroke
 Treat symptoms of PAD- functio...
BIOLOGY OF PAD IN DIABETES
Changes in arterial structure & function
Increase vascular inflammation
Derangement of the cell...
ENDOTHELIAL DYSFUNCTION IN PAD
 Increased TNF-alpha, IL-6 & circulating
adhesion molecules e.g.. VCAM,Increased PAI-1
 C...
PHYSICAL EXAMINATION
 Visual inspection of the lower extremities
 Atrophy of skin,alopecia,dystrophy of nails,coldness o...
ANKLE BRACHIAL INDEX
 It is a simple test to asses lower extremities circulation with
Doppler ultrasound probe & blood pr...
 Sometime it is useful to measure ABI before and
after exercise
 In some diabetic patient because of
sclerosis,arteries ...
KEY POINTS FOR PAD PATIENTS MANAGEMENT
 Screen for CAD & aggressive management for CAD risk factors
e.g. H.T.,Dyslipedemi...
BENEFITS OF EXERCISE IN PAD
 Lowers the blood pressure
 Improve claudication symptoms
Increase pain free & maximal walki...
CAD IN PAD PATIENTS
 Mortality rate 30% at 5 years, 50% at 10yrs. & 75% at 15yrs.
90% deaths are due to MI and Stroke
 R...
EFFECT OF TYPE 2 DIABETES & ITSEFFECT OF TYPE 2 DIABETES & ITS
DURATION ON THE RISK OF PAD INDURATION ON THE RISK OF PAD I...
BACKGROUNDBACKGROUND
 PAD is associated withPAD is associated with
↑↑ morbiditymorbidity
↑↑ risk of MI & strokerisk of MI...
AIMAIM
To assess the risk of developing PAD inTo assess the risk of developing PAD in
relation to the duration of diabetes...
RESULTS(cont.)RESULTS(cont.)
 387 cases of PAD among 48, 607 men387 cases of PAD among 48, 607 men
 Men who developed PA...
CONCLUSIONCONCLUSION
The results indicate that duration of Type 2The results indicate that duration of Type 2
diabetes is ...
SUMMARYSUMMARY
 PAD is not a major cause of mortality althoughPAD is not a major cause of mortality although
 Diabetes i...
HOW COMMON IS INTERMITTENTHOW COMMON IS INTERMITTENT
CLAUDICATION?CLAUDICATION?
 Occurs in 40-50% of PAD patientsOccurs i...
MANAGEMENTMANAGEMENT
 Risk factor modificationRisk factor modification
 Exercise therapyExercise therapy
 Antiplatelet ...
PENTOXIFYLLINEPENTOXIFYLLINE
 Hemorrheologic agentHemorrheologic agent
 Improves erythrocyte deformability, reduces bloo...
CILOSTAZOLCILOSTAZOL
 Novel agentNovel agent
 Approved by US FDA in 1999Approved by US FDA in 1999
 Only drug besides p...
UNIQUE MECHANISM OF ACTIONUNIQUE MECHANISM OF ACTION
CilostazolCilostazol
↓↓
Phosphodiesterase III inhibitorPhosphodiester...
 NO EFFECT ON BLEEDING TIMENO EFFECT ON BLEEDING TIME
 BENEFICIAL EFFECTS ON LIPIDSBENEFICIAL EFFECTS ON LIPIDS
 EXERTS...
““The unique combination of antiplatelet,The unique combination of antiplatelet,
vasodilatory, antiproliferative and lipid...
Dawson et al.
Circulation 1998; 98: 678-686
 GREATER IMPROVEMENT IN MAXIMALGREATER IMPROVEMENT IN MAXIMAL
WALKING DISTANC...
CONTRAINDICATIONSCONTRAINDICATIONS
 Hypersensitivity to the drugHypersensitivity to the drug
 Congestive heart failureCo...
1362466122 pad in diabetes
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1362466122 pad in diabetes

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1362466122 pad in diabetes

  1. 1. PHERIPHERAL ARTERY DISEASE IN DIABETES DR. S.K.SHARMA CONSULTANT ENDOCRINOLOGIST JAIPUR.
  2. 2. ADA Guidelines for PAD care inADA Guidelines for PAD care in DiabeticsDiabetics  29% prevalence of PAD in diabetics over29% prevalence of PAD in diabetics over 50 years50 years  Failing to detect PAD may lead to lowerFailing to detect PAD may lead to lower limb amputations and increased five-yearlimb amputations and increased five-year risk of myocardial infarction (MI) or stroke,risk of myocardial infarction (MI) or stroke, with a mortality rate of about 33%.with a mortality rate of about 33%.
  3. 3. PAD underdiagnosed inPAD underdiagnosed in DiabeticsDiabetics  Of all patients with PAD, half areOf all patients with PAD, half are asymptomaticasymptomatic  One third have claudicationOne third have claudication  Remaining patients have severe diseaseRemaining patients have severe disease  Peripheral Neuropathy in the diabeticsPeripheral Neuropathy in the diabetics make the condition asymptomaticmake the condition asymptomatic
  4. 4. Goals Of TreatmentGoals Of Treatment  Symptom controlSymptom control  Prevention of Limb lossPrevention of Limb loss  Reduction of other macrovascular diseaseReduction of other macrovascular disease
  5. 5. Screening & DiagnosisScreening & Diagnosis  ABI is recommended in all diabetic patientsABI is recommended in all diabetic patients older than 50 years and in those youngerolder than 50 years and in those younger than 50 years if there is coexistingthan 50 years if there is coexisting hypertension, smoking,hypertension, smoking, hypercholesterolemia, or diabetes for morehypercholesterolemia, or diabetes for more than 10 yearsthan 10 years  If normal, ABI should be repeated every 5If normal, ABI should be repeated every 5 years.years.  The ABI is 95% sensitive and almostThe ABI is 95% sensitive and almost 100%100% specific compared with angiographyspecific compared with angiography
  6. 6. Screening & Diagnosis(cont.)Screening & Diagnosis(cont.)  Functional testing with a graded treadmill isFunctional testing with a graded treadmill is useful for evaluating treatment efficacy.useful for evaluating treatment efficacy.  Duplex ultrasonography or magneticDuplex ultrasonography or magnetic resonance angiography visualize vessels andresonance angiography visualize vessels and help in surveillance for graft or stent patencyhelp in surveillance for graft or stent patency  X-ray angiography is the gold standard, butX-ray angiography is the gold standard, but the small risk of contrast-inducedthe small risk of contrast-induced nephrotoxicity precludes its routine use fornephrotoxicity precludes its routine use for diagnosisdiagnosis
  7. 7. Treatment of Asymtomatic PADTreatment of Asymtomatic PAD in Diabeticsin Diabetics  Smoking cessationSmoking cessation  Preventive foot carePreventive foot care  Maintaining HbAMaintaining HbA1C1C at less than 7%at less than 7%  Blood pressure should be aggressivelyBlood pressure should be aggressively managed, maintaining levels at less thanmanaged, maintaining levels at less than 130/80 mm Hg130/80 mm Hg  LDL cholesterol levels should be maintainedLDL cholesterol levels should be maintained at less than 100 mg/dLat less than 100 mg/dL  Antiplatelet therapy : 75 mg daily ofAntiplatelet therapy : 75 mg daily of clopidogrelclopidogrel better reduces risk of ischemicbetter reduces risk of ischemic events compared with 325 mg daily of aspirinevents compared with 325 mg daily of aspirin
  8. 8. Treatment of Symptomatic PADTreatment of Symptomatic PAD in Diabeticsin Diabetics  Customized footwear to reduce pressure forCustomized footwear to reduce pressure for neuroischemic limbsneuroischemic limbs  Supervised exercise therapy (intermittentSupervised exercise therapy (intermittent treadmill walking 3 times per week)treadmill walking 3 times per week)  CilostazolCilostazol is the drug of choice overis the drug of choice over pentoxifylline for improvement of walkingpentoxifylline for improvement of walking distance, functional status, and quality of lifedistance, functional status, and quality of life  CLI requires surgical treatment when medicalCLI requires surgical treatment when medical management with debridement, nonadherentmanagement with debridement, nonadherent dressings, and adjunctive wound healingdressings, and adjunctive wound healing techniques failstechniques fails
  9. 9. Treatment of Symptomatic PADTreatment of Symptomatic PAD in Diabetics(cont.)in Diabetics(cont.)  For all infections, incision and drainage is theFor all infections, incision and drainage is the treatment of choicetreatment of choice  Major amputation is indicated only when thereMajor amputation is indicated only when there is overwhelming infection threatening theis overwhelming infection threatening the patient's lifepatient's life  Limb revascularization indicated inLimb revascularization indicated in a) CLI resistant to conservative therapya) CLI resistant to conservative therapy b) Availability of autologous veinb) Availability of autologous vein c) Absence of irreversible gangrenec) Absence of irreversible gangrene
  10. 10. SUMMARYSUMMARY  Screening with ABI should be conducted in allScreening with ABI should be conducted in all diabetic patients older than 50 years and in thosediabetic patients older than 50 years and in those younger than 50 years with other risk factorsyounger than 50 years with other risk factors (hypertension and smoking, hypercholesterolemia,(hypertension and smoking, hypercholesterolemia, and diabetes for more than 10 years).and diabetes for more than 10 years).  Primary prevention is key and achieved byPrimary prevention is key and achieved by addressing other risk factors, including smoking,addressing other risk factors, including smoking, hypertension, glycemic control, antiplatelet therapy,hypertension, glycemic control, antiplatelet therapy, and foot care.and foot care.  CilostazolCilostazol is the drug of choice over pentoxifylline foris the drug of choice over pentoxifylline for improvement of walking distance, functional status,improvement of walking distance, functional status, and quality of lifeand quality of life
  11. 11. PAD Atherosclerotic occlusive disease of the lower extremities Epidemiology USA – 12 million people suffering from PAD 20% of symptomatic PAD had diabetes and many more asymptomatic At the time of diagnosis of diabetes PAD- 8% 10 years after PAD- 15% 20 years after PAD –45% Risk factor Lower extremity amputation Marker of atherothrombotic disease in systemic vascular accompanied by CAD CVD RENAL VESSEL Amputation prevalence in diabetes –3% I.e.8/1000 pts./year.
  12. 12. PAD IN DIABETES In diabetes risk of PAD Age Duration of diabetes Pheripheral Neuropathy Ethnic group– African, American & Hispanics
  13. 13. PREVALENCE OF PAD IN INDIAPREVALENCE OF PAD IN INDIA  CUPS; n=631CUPS; n=631  Overall prevalence of PAD=3.2%Overall prevalence of PAD=3.2% PAD prevalencePAD prevalence Normal glucoseNormal glucose Impaired glucoseImpaired glucose DiabetesDiabetes tolerance (n=517)tolerance (n=517) tolerance (n=34)tolerance (n=34) (n=80)(n=80) 2.7%2.7% 2.9%2.9% 6.3%6.3%  Prevalence of PAD in newly diagnosedPrevalence of PAD in newly diagnosed subjects was 3.5% vs 7.8% in knownsubjects was 3.5% vs 7.8% in known diabetic subjectsdiabetic subjects Diabetes Care 2000; 23: 1295-1300
  14. 14. PREVALENCE OF PAD IN INDIAPREVALENCE OF PAD IN INDIA (contd)(contd) Age groupAge group Normal glucoseNormal glucose GlucoseGlucose (yrs)(yrs) tolerance intolerancetolerance intolerance 31-5031-50 1.5%1.5% 2.1%2.1% 51-7051-70 3.4%3.4% 6.3%6.3% >70>70 12.5%12.5% 17.6%17.6% Diabetes Care 2000; 23: 1295-1300
  15. 15. In diabetes - Femoral,popliteal & tibial vessel (below the knee) In smokers - More proximal disease Aorta-ilio femoral vessel In diabetes – Prevelence of PAD mostly asymptomatic Pain perception blunted by neuropathy More changes of ischemic ulcers or gangrene
  16. 16. IMPORTANCE OF DIAGNOSIS OF PAD IN DIABETES  Identify patient with high risk of MI,Stroke  Treat symptoms of PAD- functional disability and limb loss  To identify subclinical disease & preventive measures to avoid limb threatning ischemia  Presentation more subtle in diabetes  Lesions are more diffuse and distal v/s in non diabetics
  17. 17. BIOLOGY OF PAD IN DIABETES Changes in arterial structure & function Increase vascular inflammation Derangement of the cellular component of vasculature Alteration in blood cells- haemostatic factors Accelerated atherosclerosis – poor outcome Increase CRP – marker Endothelial cell receptors -- apoptosis oxidised LDL procoagulants decrease e-NOS PAI-I
  18. 18. ENDOTHELIAL DYSFUNCTION IN PAD  Increased TNF-alpha, IL-6 & circulating adhesion molecules e.g.. VCAM,Increased PAI-1  Chronic hyperglycemia results in glycosylation of protein formation of AGE, increased oxidative stress induced vascular inflammation via receptar for AGE(RAGE)
  19. 19. PHYSICAL EXAMINATION  Visual inspection of the lower extremities  Atrophy of skin,alopecia,dystrophy of nails,coldness of the toes & change in color  Hypoxia – vasodilation in the dependent position(rubor)  Rapid balancing with elevation  Feeble or absent pulsation –femoral,paplioteal,dorselis pedis and posterior tibial  Arterial bruits
  20. 20. ANKLE BRACHIAL INDEX  It is a simple test to asses lower extremities circulation with Doppler ultrasound probe & blood pressure cuff  In which systolic pressure of both brachial arteries of arms & posterior tibial & dorselis pedis arteries of both lower limb is measured  ABI is ratio of Ankle systolic pressure Brachial systolic pressure ABI Sevearity of PAD 0.90—1.30 Normal 0.70--- 0.89 Mild 0.40--- 0.69 Moderate < 0.40 Severe
  21. 21.  Sometime it is useful to measure ABI before and after exercise  In some diabetic patient because of sclerosis,arteries are noncompressible and show abnormal high ABI(>1.3)  In such patient arterial duplex ultrasound,pulse volume waveform analysis or toe brachial index in measured
  22. 22. KEY POINTS FOR PAD PATIENTS MANAGEMENT  Screen for CAD & aggressive management for CAD risk factors e.g. H.T.,Dyslipedemia, Glucose intolerance & Smoking  No pharmacological therapy e.g. Weight loss,Smoking Cessation & structured exercise programme including walking programme  ACE-I Antihypertensive agent of choice(renal function should be followed closely because atherosclerotic renal artery sclerosis / HOPE-14.1% v/s 17.7% with placebo ; 40% and 10% bilateral renal artery stenosis)  Treatment of H.T. in PAD patients reduces the risk of MI,Stroke,HF & death  All patients with PAD should be on an antiplatlet agent
  23. 23. BENEFITS OF EXERCISE IN PAD  Lowers the blood pressure  Improve claudication symptoms Increase pain free & maximal walking distance  Improve quality of life  Improve survival  Lowers TG’s and raises HDL – Chloe.  Improves Glucose tolerance and Insulin resistance
  24. 24. CAD IN PAD PATIENTS  Mortality rate 30% at 5 years, 50% at 10yrs. & 75% at 15yrs. 90% deaths are due to MI and Stroke  Relative risk of dying of CAD in patientswith PAD is 6-7 times  ABI prediction of cardiovascular mortality –25% mortality rate at 4 yrs. In women with ABI of <0.9 DIABETES AND PAD  35-40% of patients with PAD have Diabetes mellitus
  25. 25. EFFECT OF TYPE 2 DIABETES & ITSEFFECT OF TYPE 2 DIABETES & ITS DURATION ON THE RISK OF PAD INDURATION ON THE RISK OF PAD IN MENMEN Am J Med. 2004;116:236-240Am J Med. 2004;116:236-240
  26. 26. BACKGROUNDBACKGROUND  PAD is associated withPAD is associated with ↑↑ morbiditymorbidity ↑↑ risk of MI & strokerisk of MI & stroke ↑↑ risk of amputationrisk of amputation  Incidence of PAD is linked with incidenceIncidence of PAD is linked with incidence of DMof DM  What about duration of diabetes & PAD?What about duration of diabetes & PAD?
  27. 27. AIMAIM To assess the risk of developing PAD inTo assess the risk of developing PAD in relation to the duration of diabetes amongrelation to the duration of diabetes among men in the Health Professionals Follow-upmen in the Health Professionals Follow-up StudyStudy
  28. 28. RESULTS(cont.)RESULTS(cont.)  387 cases of PAD among 48, 607 men387 cases of PAD among 48, 607 men  Men who developed PAD were older, consumedMen who developed PAD were older, consumed more alcohol, smoked more, took more aspirin,more alcohol, smoked more, took more aspirin, physically less active and more likely to havephysically less active and more likely to have hypertension and hypercholesterolemiahypertension and hypercholesterolemia  The age adjusted RR of PAD among diabeticThe age adjusted RR of PAD among diabetic compared with non diabetic is 3.39 (95% CI)compared with non diabetic is 3.39 (95% CI)  If all other risks are adjusted the RR becameIf all other risks are adjusted the RR became 2.61 (95% CI)2.61 (95% CI)
  29. 29. CONCLUSIONCONCLUSION The results indicate that duration of Type 2The results indicate that duration of Type 2 diabetes is associated strongly with the risk ofdiabetes is associated strongly with the risk of developing PADdeveloping PAD
  30. 30. SUMMARYSUMMARY  PAD is not a major cause of mortality althoughPAD is not a major cause of mortality although  Diabetes increases the risk of amputation 3 foldsDiabetes increases the risk of amputation 3 folds compared to non-diabeticscompared to non-diabetics  PAD is strongly associated in diabetics withPAD is strongly associated in diabetics with hypertension and smoking habitshypertension and smoking habits  An advantage of this study was the relatively longAn advantage of this study was the relatively long follow-ups (12 years)follow-ups (12 years)  Awareness of these effects by patients and healthAwareness of these effects by patients and health professionals will lead to earlier detection of PADprofessionals will lead to earlier detection of PAD and its effective managementand its effective management
  31. 31. HOW COMMON IS INTERMITTENTHOW COMMON IS INTERMITTENT CLAUDICATION?CLAUDICATION?  Occurs in 40-50% of PAD patientsOccurs in 40-50% of PAD patients  Relatively common; occurs in 5% ofRelatively common; occurs in 5% of adults > 65 yearsadults > 65 years  Higher rates in older adults, smokers andHigher rates in older adults, smokers and diabeticsdiabetics  Annual incidence is 2% in people aged >Annual incidence is 2% in people aged > 65 years65 years Curr Med Res Opin 2002; 18: 479-487Curr Med Res Opin 2002; 18: 479-487 Am J Cardiol 2001; 87 (Suppl): 14 D-18 DAm J Cardiol 2001; 87 (Suppl): 14 D-18 D
  32. 32. MANAGEMENTMANAGEMENT  Risk factor modificationRisk factor modification  Exercise therapyExercise therapy  Antiplatelet therapyAntiplatelet therapy  Medical therapy targeted at symptomsMedical therapy targeted at symptoms  Revascularisation proceduresRevascularisation procedures
  33. 33. PENTOXIFYLLINEPENTOXIFYLLINE  Hemorrheologic agentHemorrheologic agent  Improves erythrocyte deformability, reduces bloodImproves erythrocyte deformability, reduces blood viscosity and decreases platelet reactivity and plasmaviscosity and decreases platelet reactivity and plasma hypercoagulabilityhypercoagulability  First drug approved for intermittent claudication in 1984First drug approved for intermittent claudication in 1984  ‘‘De factoDe facto’ standard’ standard ““Pentoxifylline is no longer recommended for first-linePentoxifylline is no longer recommended for first-line therapy for most patients with intermittent claudication”therapy for most patients with intermittent claudication” Am J Cardiol 2001; 87 (suppl): 14D-18D
  34. 34. CILOSTAZOLCILOSTAZOL  Novel agentNovel agent  Approved by US FDA in 1999Approved by US FDA in 1999  Only drug besides pentoxifyllineOnly drug besides pentoxifylline specifically indicated for intermittentspecifically indicated for intermittent claudicationclaudication
  35. 35. UNIQUE MECHANISM OF ACTIONUNIQUE MECHANISM OF ACTION CilostazolCilostazol ↓↓ Phosphodiesterase III inhibitorPhosphodiesterase III inhibitor ↓↓ ↑↑cAMP levelscAMP levels PlateletsPlatelets Vascular smoothVascular smooth musclemuscle ↑↑LipoproteinLipoprotein lipase activitylipase activity ↓↓TG synthesisTG synthesis ↓↓ PlateletPlatelet aggregationaggregation  VasodilationVasodilation  ↑↑ peripheral blood flowperipheral blood flow  Antiproliferative effectAntiproliferative effect ↓↓ TGTG ↑↑ HDLHDL
  36. 36.  NO EFFECT ON BLEEDING TIMENO EFFECT ON BLEEDING TIME  BENEFICIAL EFFECTS ON LIPIDSBENEFICIAL EFFECTS ON LIPIDS  EXERTS ANTIPROLIFERATIVE EFFECTSEXERTS ANTIPROLIFERATIVE EFFECTS  CAUSES REGRESSION OF CAROTIDCAUSES REGRESSION OF CAROTID ATHEROSCLEROSISATHEROSCLEROSIS Hemostasis 1999;29:269-276
  37. 37. ““The unique combination of antiplatelet,The unique combination of antiplatelet, vasodilatory, antiproliferative and lipid-vasodilatory, antiproliferative and lipid- modifying effects of cilostazol make it anmodifying effects of cilostazol make it an attractive agent for use in PAD patientsattractive agent for use in PAD patients with intermittent claudication”with intermittent claudication” Ann Pharmacother 2001; 35: 48-56Ann Pharmacother 2001; 35: 48-56
  38. 38. Dawson et al. Circulation 1998; 98: 678-686  GREATER IMPROVEMENT IN MAXIMALGREATER IMPROVEMENT IN MAXIMAL WALKING DISTANCE EVEN AT TROUGHWALKING DISTANCE EVEN AT TROUGH  IMPROVES ANKLE-BRACHIAL INDEXIMPROVES ANKLE-BRACHIAL INDEX  INCREASE PAIN FREE AND MAXIMALINCREASE PAIN FREE AND MAXIMAL WALKING DISTANCEWALKING DISTANCE  IMPROVE FUNCTIONAL ABILITY &IMPROVE FUNCTIONAL ABILITY & QUALITY OF LIFE (ASSESSED BYQUALITY OF LIFE (ASSESSED BY QUESTIONNAIRES)QUESTIONNAIRES)
  39. 39. CONTRAINDICATIONSCONTRAINDICATIONS  Hypersensitivity to the drugHypersensitivity to the drug  Congestive heart failureCongestive heart failure WARNINGS & PRECAUTIONSWARNINGS & PRECAUTIONS  Pregnancy: Category CPregnancy: Category C  Nursing mothersNursing mothers

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