ADR Common Drug -Induced Organ Disorders
Transcript of ADR Common Drug -Induced Organ Disorders
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ADR common Drug -Induced Organ Disorders
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ADR common Drug -Induced Organ Disorders
• Cardiovascular Disorders• Hematological Disorders• Renal Disorders• Liver Disorders
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Cardiovascular Disorders
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Cardiovascular Disorders
• Rate & Rhythm
Patient Complain Fatigue Dyspnea Othopnea Peripheral
Edema
RateNormal 60-100 beat/min
Tarchy >100 beat/min
Brady < 60 beat/min
Rhythm Regular vs Irregular
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Cardiovascular Disorders
• Blood Pressure Patient Complain Dizziness Syncope Lightheadedness Headache• Miscellaneous Chest pain
Normal < 120/80 mmHg
Hyper >= 140/90 mmHg
Hypo < 90/60 mmHg
with symptom
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Type of Drug-induced CVD• Disturbance on BP regulation
Hypertension Hypotension• Heart failure• MI• Rhythm disturbance• Myocarditis• Vasculopathy Vasculitis Vasospasm• Disturbance of Haemostatic balance
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Common Abnormal EKG
Normal Range• P-R 120-200 millisecond• Q-T < 440 millisecond• Q-R-S < 100 millisecond
Hyper K+ T- wave สู�งมาก
S/E Spironolactone
Hyper K+ QRS abnormal
QRS abnormal No-signal
U wave สู�งผิดปกติTorsade de Pointes
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Focus on DrugsNSAID Heart failure *** พบบ�อยที่��สู�ด Increase BP MI Mech. Decrease Renal Perfusion
Increase SNS activity Decrease Renal Blood flowIncrease contractility &Heart Rate Increase Renin release Increase Angiotensin II Na retention
Volume Overload/Edema
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NSAIDs &CVD-ADR Risk Factor
• Patient factors : Heart, Renal Impair• Drug factor : High dose ,Interval of
Dosing ,Prolonged treatment ,PK/PD (long half life)
• CVD-ADR Risk : Naproxen < Diclofenac < Ibuprofen• Na Retention Effect: Selective Cox-2 = Non-selective Cox-2 (bz effect from PGE2)Dose & Duration ADR
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Viagra (Sidenafil) & CVD-ADR
• Sidenafil (Inh.PDE5 Increase cGMP Decrease BP)
• Sidenafil+ Nitrates (:ISDN SL ) ควรให้�ห้�างก�น > 24 hr.(Sidenafil half life =3-5 hrs, duration = 4-6+
hrs.)
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Alpha blocker (in BPH)
Suggest : Selective -Alpha Blocker (:Tamsulosin, Alsulosin)
จะไม่�ค่�อยลดค่วาม่ด�นโลหิ�ตม่ากน�ก
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QT interval Prolongation
• Prolongation of Ventricular repolarization(cause arrhythmias,esp. torsades de pointes)• Factors Affecting QTc IntervalSex : women > menAge : elderly > youngElectrolyte imbalance :Hypo K ,Hypo MgPresence of CVDD/IGeneticsConcomitant use of dugs prolonging QTc
interval
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Drugs causing QTc prolongation
• Astemizole• Terfenadine• Cisapride• Grepafloxacin• Gatifloxacin• Moxifloxacin• Sparfloxacin
• Erythromycin• Clarithromycin• Amiodarone• Procainamide• Quinidine• Sotalol• TCA• Antipsychotics
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Mechanism of Drug-induced Arrhythmias
• Blocking of Na channel• Blocking of rectifier potassium channel (IKr)• Result:QT prolongation early after
depolarization + imhomogeneity of ventricular recovery Polymorphic ventricular tarchycardia Torsade de pointes
• Not cases of QTc prolongation will develop Torsade
• Torsade case mostly occurred when QTc> 500 ms• Symptoms of torsade :Dizziness,
lightheadedness, palpitations, presyncope, syncope
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Typical Antipsychotic vs QTc ProlongationDrug
Low potency phenothiazinesChlorpromazine
ThioridazineMesoridazine
High potency phenothiazinesPerphenazineFluphenazine
PimozideButyrophenones
HaloperidolDroperidol
Risk
Rare or UncertainWorst
Problematic
Rare or UncertainRare or Uncertain
Worst
Rare or UncertainWorst
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Management of Drug-induced QTc prolongation
• D/C culprit drugs immediately• Control the Arrhythmia by increasing the
heart rate .• Electrolyte abnormalities should be
corrected.• MgSO4 infusion may effectively terminate
arrhythmia ,even in presence of normal Mg levels.
• Antiarrhythmic drugs may worsen the problem and should be avoided
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Myocarditis/Cardiomyopathy
• Clozapine is only drug implicated (incidence : 0.29%)
• Myocarditis occur relatively soon after therapy start (2.-3 wks)Histopathology suggests immunological process
• Cardiomyopathy :Time to onset =12 month• Signs/symptoms of
Myocarditis/CardiomyopathyShortness of breathDyspnea on exertionOrthopnea, paroxysmal dyspneaFatiguePeripheral edema
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Myocardial Ischaemia• Adrenosine• Amphetamines• Beta-agonists• Caffeine• Dipyridamole• Ergotamine• Nifedipine(short
acting)• Theophylline• Thyroxine• Verapamil
• Fluorouracil• Vincristine• Vinblastine
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Drug induced Hematological Disorders
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Type of Hematological disorder
• AnemiaImpair erythropoiesis relate anemiaMegaloblastic anemiaHemolytic anemia (HA):G6PD, Immune typeMethemoglobinemia
• Neutropenia/Agranulocytosis Febrile neutropenia
• ThrombocytopeniaThrombotic thrombocytopenic purpura(TTP)
• Aplastic anemia• Pure red cell aplasia (PRCA)
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Clinical course depends on
• สูภาวะที่างคลินกเดมของผิ��ป#วย (ห้ากภาวะโภชนาการด� จะเกดอาการไม�พ(งประสูงค)ช�ากว�า)
• ปรมาณยาแลิะระยะเวลิาที่��ได�ร�บยา (ในกรณ�ที่��เป,นชนด Dose dependent)
• ชนดของเซลิลิ)เม.ดเลิ/อดที่��เกดอาการไม�พ(งประสูงค)(ซ(�งม�อาย�ติ�างก�น)• ผิลิที่��เกดข(0นน�0นเกดที่��ระด�บ precursor ระด�บใดห้ากเป,นระด�บติ�นก.
จะสู�งผิลิเสู�ยมาก ห้ากเป,นช�วงปลิายก.สู�งผิลิไม�มากน�ก**ห้ากไม�น�บ ADR จากเคม�บ1าบ�ดถื/อว�า ADR ระบบน�0พบน�อย**พบมากในกลิ��มผิ��สู�งอาย�แลิะเด.ก**ห้ากเกดในผิ��ป#วยที่��ม�ภาวะผิดปกติที่างระบบเลิ/อดอย��แลิ�วจะเพ�ม
อ�ติราติายสู�งข(0นการพยากรณ)โรคไม�ด�
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Drug induced Anemia 4 type
1. Impaired erythropoiesis related anemia
2. Anemia due to impair erythropoiesis
3. Megaloblastic anemia4. Hemolytic anemia
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Impaired erythropoiesis related anemia
• เกดการกดไขกระด�กช��วคราว• Incidence , onset, severity จะข(0นอย��ก�บ
สูภาวะที่างคลินกเดมของผิ��ป#วย• Clinical feature ที่��บ�งบอกค/อ
*Hb,Hct ลิดลิง - +/ abnormal RBC indices*blood smear:less RBC +/- abnormal morphology (microcytic, microchromic,anisocytic)
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Management
• ใหิ�ค่วาม่สำ�าค่�ญที่��การต�ดตาม่หิล�งจากได�ร�บยา• อาจจ�าเป็"นต�องใหิ�เล#อดหิาก Hb < 10 gm/dl
เน#�องจากเสำ��ยงก�บภาวะ Hypoxia• Erythropoietin ไม่�จ�าเป็"นต�องใช้�ในผู้'�ป็(วยที่��ไม่�
ร)นแรงเน#�องจากหิล�งหิย)ดยาอาการก+จะด�ขึ้-.นเอง• แต�อาจต�องรอค่อยเพื่#�อใหิ�กล�บม่าสำ'�สำภาวะป็กต�
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Drug induced Megaloblastic anemiaMegaloblastic anemia (ภาวะซ�ดที่��ม�เม.ดเลิ/อดให้ญ่�กว�าปกติ การที่1างาน
ไม�ด�)สูาเห้ติ� 1.ยาที่1าให้�การสูร�าง DNA & RNA ผิดปกติ 2.ยาที่1าให้�เกดการขาด Vit B12 & Folic ซ(�งเป,นป5จจ�ยสู1าค�ญ่ในการเพ�ม
จ1านวนเซลิลิ) ได�แก�กลิ��มยา 1.Antimetabolites chemotherapy: MTX, 5-FU 2.Sulfa & Trimethoprim ** พบบ�อยในผิ��ป#วย HIV3.Anticonvulsant: Phenytoin, Barbiturate, Clinical feature ม�กค�อยๆเกดแลิะอาการไม�ร�นแรงIncidence , onset, severity จะข(0นอย��ก�บสูภาวะที่างคลินกเดมของผิ��
ป#วยPale, Blood smear: large RBC, Polynucleated PMNRBC indices:MCV > 115-120 fl ,BMA:large megaloblastอาจพบอาการแสูดงของการที่��ม� Vit B12& Folic ติ1�าได�
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Management
• ไม�เร�งด�วน แติ�ให้�เน�นการป7องก�นแลิะติดติามภาวะเลิ/อดของผิ��ป#วย
ถื�าเกดจากยาที่1าให้�ขาด folic• Severe or High risk case Folinic acid
or rescuvolin• Mild to Moderate anemia Folic acid**Concern D/Iถื�าเกดจากยาที่1าให้�ขาด Vit B 12• Vit B 12 supplement 1-2 dose
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Drug induced Methemoglobin anemia
• Hb-Fe2+ Hb-Fe3+ (Methemoglobin)
เกดภาวะ Tissue Hypoxia Oxidant Drug
Antimalarial Drug
Benzocaine
Clofazimine
Dapsone
Phenazopyridine
High dose Sulfa
Nitrate/Nitrite
Paraquat
•Serum methemoglobin >10%
•Anemia/Cyanosis
Management
Methylene blue
1-2 mg/kg over 5 min
If G6PDHemolytic ***
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Drug induced Hemolytic anemia
Peripheral RBC destruction
Drug increase risk of hemolysis individual with heredity RBC defect :
Metabolic type Hemolytic anemia
Immune type Hemolytic anemia
Drug induce antibody against RBC
G6PD
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Drug induced Hemological defect in
G6PD
Severity depends on
1.ชนดแลิะขนาดยา2 .ป5จจ�ยร�วมอ/�นๆ เช�นการติดเช/0อ3.ระด�บความร�นแรงของ G6PD deficiency level 4 ระด�บ
Clinical feature
RBC count,Hb.Hct
Indirect billirubin, % reticulo count
Blood smear:usually normochromic anemia, poikilocytic,spherocytic,
ติ�วเห้ลิ/องติาเห้ลิ/อง Dark urine
RBC แติก
Metabolic type Hemolytic anemia
X-link gene disorder 10% in black American, Asians, Mediteraneans
G6PD Def. Low Antioxidant Increase Methemoglobin RBC แติกง�าย
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G6PD Deficiency
Drugs Able to Induce Hemolysis in G6PD-Deficient Patients
pentose phosphate pathway
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Drug induced Immune type Hemolytic anemia•High affinity hapten type
[Drug-moiety on RBC]-Ab to RBC
(eg. High dose penicillin,tetracycline, tolbutamide)
•Innocent bystander reaction
[Drug-Ab]-RBC (eg.2nd 3rd Ceph.)
•Ag-Ab Immune cpx.
Auto against RBC (eg. Cefotetan, ceftriaxone)
Clinical feature-+/ ติ�วเห้ลิ/องติาเห้ลิ/อง - +/ Dark urine
RBC count ,Hb.Hct
Indirect billirubin,% reticulo count
Blood smear: normochromic anemia,poikilocytic,spherocytic,
•Slow onset
•moderate- severe Hemolytic
Immune type Hemolytic anemia
•sudden onset
•severe Hemolytic - +/ renal fail.
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Management
• เลิ��ยงยาที่��ควรห้ลิ�กเลิ��ยงในผิ��ป#วย G6PD def.• ห้ย�ดยาที่��ที่1าให้�เกด Immune type Hemolytic
anemia แลิ�วเปลิ��ยนยาที่างเลิ/อกแที่น ห้�าม rechallenge
• ให้� PRC ห้าก Hb ติ1�ามากแติ�ควรระว�งห้ากให้�ในขณะที่�� Active อย��ถื�าม�แติกเพ�มอาจเกด renal failure เพ�มข(0นได�
• ประสูที่ธิผิลิการใช� steriod ใน Autoimmune ย�งไม�ช�ดเจน
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Drug induced Neutropenia or Agranulocytosis
Leukopenia = WBC < 3000/µl
Granulocytopenia =granulocyte<1500/µl
Neutopenia =ANC< 1500/µl
Agraulocytosis =ANC < 500/µl
ANC = WBC [%N+%band]
(if band cell >= 10%)
ANC = WBC *%N
(if band cell <10%)
•Rapid onset (2-14 day) in direct toxic or hypersens
•Delay onset in Immune type(คร�0งแรก)•Drug attack peripherally mature
myeloid
•Hypersens
•Immun mediated reaction Infection
WBC, %N ลิดลิง
ห้ย�ดยา ใช�ยาให้ม�ที่��โครงสูร�างแติกติ�าง
Mech.
Clinical Features
management
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Drug induced Thrombocytopenia
Mech.1.Direct toxic to thrombopoiesis/
peripheral platelet2.Immunoreaction to peripheral
plateletHapten-type Rx(Heparin, abciximab)Innocent bystander type (quinidine
high dose)Drugs induced Ab against platelet**Other factors: heavy alcohol,hepatic disease
•Impair coagulation•ห้ากม�ป5ญ่ห้าเลิ/อดออกอย�� ภาวะโรคก1าเรบได�•ความเสู��ยงเพ�มข(0นในผิ��ป#วยที่��ใช�ยากลิ��ม Anticoagulant
Clinical Feature•Plt.count < 100,000/µl(normal:150,000-300,000/µl)•If < 50,000 spontanous bleeding•Sign of Impair coagulation(petechia,bruisebleeding)
•ห้ย�ดยาที่��สูงสู�ย•ให้�เกลิ.ดเลิ/อด (ห้ากเกดจาก immuneไม�ม�ประโยชน))•ห้�าม rechallenge(immune)•ระว�ง IM,SCbleeding
management
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Heparin induced Thrombocytopenia (HIT)• Incident 0.3- 0.7%
• Course of reaction: 2 type • HIT type I: mild, reversible, non- immune
type (onset 2-4 days) due to platelet clump
• HIT type II :Severe immune mediated (onset 5-10 day(1st exposure) Next timerapid) **concern Hep-lock,catheter
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Heparin induced Dual Thrombocytopenia /Embolism
Platelet-Heparin-PF4
IgG +
Immune complex-Platelet
Platelet-Heparin-PF4
IgG
Thrombocytopenia
Thrombosis
Stroke, arterial occlusion*
*HEP treatment failure ?
Splenic macrophages
Incidence 75-88%
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LMWH induced Thrombocytopenia
•Incidence < Heparin
•Mech:~ HIT
•LMWH: Not recommend to use alternative in pt. HITAbciximab induced Thrombocytopenia•Incidence :Abciximab alone < 1%,Hep alone 0.3-0.7% ,Abciximab+Hep 1.3-1.6%•Mech:Non-immune dose-dependent Hapten-type: [Abciximab-GPIIb/IIIa]-Ab
Thrombocytopenia
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Drug Induced Thrombotic Thrombocytopenic Purpura (TTP)
5 Cardinal Features
•Thrombocytopenia
•Microangiopathic hemolytic anemia RBC fragment & organlesion
•Neurological changes
•Progressive renal failure
•Fever
Incidence 3.7 cases/1 million/year
Mortality rate 10-20%
Onset < 1 mo.
(not relate to pre-treatment plt.level)
Drug induced TTP•Ticlopidine/ Clopidogrel•Penicillin•Some antineoplastics•Oral contraceptive drugs
•ห้ย�ดยา•ให้� plasma ไปจน recovery
management
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Drug Induced Aplastic anemia•BM suppression rapid & seriously impair hematopoiesis
•Cardinal feature = 2 from 3 defects with BM aplasiaClinical feature•Sign & symptom of anemia,granulocytopenia,thrombocytopenia depending on affected cell line•BM aspiratehypocellular•10-40% died from complication (2/3bac./fungal inf.) •Massive bleeding•Onset:variable av.~6-8 wk. usually after drug D/C
Mech.•Dose dependent,reversible direct damage•Idiosyncratic possibly from toxic metabolite•Immune Type AA
Incidence :0.5-7.8 cases/million/year(25-50% drug)
WBC <3,000, Plt. <50,000 Hb<10 g/dl, Reticulocyte<30,000
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Drug Induced Aplastic anemia
•ห้ย�ดยาที่�นที่�•Supportive treatment similar to anemia, thrombocytopenia & agranulocytosis•Major treatment to BM aplasia including 1.immunosuppressant: methyprednisolone 1-2 mg/kg in severe case or > 45 years 2.Alternative treatments: ATG , ALG, Cyclosporin, androgen
management
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Drug induced Pure Red Cell Aplasia (PRCA)PRCA = Anemia that affect only erythroid cell
line Condition induce PRCA
•Autoimmune disease.
•Viral infection:Hepatitis B, Parvovirus B19
•Immunocompromise status
•Post-transplantation
•Neoplasm:Thymus carcinoma, B-LL
•Folic acid Def.
•PRCA inheritant
Drug induce PRCA
•Immunosupressive ag.
•Antiviral drugs
•Anti-infective ag.
•Anticonvulsants
•Drug related to Folic acid def.
•Erythropoetin like products:
• EPOα>β
•Other:Alloprinol, α-methyldopa
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Drug induced Pure Red Cell Aplasia (PRCA)Clinical feature
Reduction of RBC count ,Hb, Hct, reticulocyte count < 1%+/- moderate granulocytopenia or thrombocytopeniaNormal or Low billirubinBlood smear: less cells may be smallBM aspirate: hypocellular erythroid cellsMech.•Hypersensitivity•Direct toxic to erythroid cell line•Immune induction Immune cpx.of drug/metabolite(eg.EPO α Hapten (eg.diphenylhydantoin)*may be Folic def. to induce aplastic crisis
•ห้ย�ดยาที่��สูงสู�ยเพ/�อก1าจ�ดป5จจ�ยเสู��ยง•Blood cell supplement maintain O2 supply
•ติ�องรอเวลิาในการกลิ�บสู��สูภาวะปกติ(ว�น-สู�ปดาห้))
management
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Drug induced renal and Liver disorder are coming soon ^^”