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ADR common Drug -Induced Organ Disorders

ADR common Drug -Induced Organ Disorders


Cardiovascular Disorders Hematological Disorders Renal Disorders Liver Disorders

Cardiovascular Disorders

Cardiovascular Disorders
Rate & Rhythm
Patient Complain Fatigue
Rate Normal 60-100 beat/min
Tarchy >100
beat/min

Dyspnea Brady < 60 beat/min Othopnea Rhythm Peripheral Edema Regular vs Irregular

Cardiovascular Disorders
Blood Pressure Patient Complain Dizziness Syncope Lightheadedness Headache

Normal < 120/80


Hyper >= 140/90 Hypo < 90/60

mmHg mmHg

mmHg

Miscellaneous Chest pain

with symptom

Type of Drug-induced CVD


Disturbance on BP regulation Hypertension Hypotension Heart failure MI Rhythm disturbance Myocarditis Vasculopathy Vasculitis Vasospasm Disturbance of Haemostatic balance

Common Abnormal EKG


Normal Range
P-R 120-200 millisecond Q-T < 440 millisecond Q-R-S < 100 millisecond
QRS abnormal No-signal U wave Torsade de Pointes Hyper K+ T- wave

S/E Spironolactone Hyper K+ QRS abnormal

NSAID
Mech.

Focus on Drugs
MI
Heart failure *** Increase BP
Decrease Renal Perfusion Decrease Renal Blood flow Increase Angiotensin II Na retention

Increase SNS activity Increase contractility &Heart Rate Increase Renin release

Volume Overload/Edema

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

Viagra (Sidenafil) & CVD-ADR


Sidenafil
(Inh.PDE5 Increase cGMP Decrease BP)

Sidenafil+ Nitrates (:ISDN SL ) > 24 hr. (Sidenafil half life =3-5 hrs, duration = 4-6+ hrs.)

Alpha blocker (in BPH)


Suggest : Selective -Alpha Blocker
(:Tamsulosin, Alsulosin)

QT interval Prolongation
Prolongation of Ventricular repolarization (cause arrhythmias,esp. torsades de pointes) Factors Affecting QTc Interval
Sex : women > men Age : elderly > young Electrolyte imbalance :Hypo K ,Hypo Mg Presence of CVD D/I Genetics Concomitant use of dugs prolonging QTc interval

Drugs causing QTc prolongation


Astemizole Terfenadine Cisapride Grepafloxacin Gatifloxacin Moxifloxacin Sparfloxacin Erythromycin Clarithromycin Amiodarone Procainamide Quinidine Sotalol TCA Antipsychotics

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

Typical Antipsychotic vs QTc Prolongation


Low potency phenothiazines Chlorpromazine Thioridazine Mesoridazine High potency phenothiazines Perphenazine Fluphenazine Pimozide Butyrophenones Haloperidol Droperidol

Drug

Risk
Rare or Uncertain Worst Problematic Rare or Uncertain Rare or Uncertain Worst Rare or Uncertain Worst

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

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/Cardiomyopathy Shortness of breath Dyspnea on exertion Orthopnea, paroxysmal dyspnea Fatigue Peripheral edema

Myocardial Ischaemia
Adrenosine Amphetamines Beta-agonists Caffeine Dipyridamole Ergotamine Nifedipine(short acting) Theophylline Thyroxine Verapamil Fluorouracil Vincristine Vinblastine

Drug induced Hematological Disorders

Type of Hematological disorder


Anemia Impair erythropoiesis relate anemia Megaloblastic anemia Hemolytic anemia (HA):G6PD, Immune type Methemoglobinemia Neutropenia/Agranulocytosis Febrile neutropenia Thrombocytopenia Thrombotic thrombocytopenic purpura(TTP) Aplastic anemia Pure red cell aplasia (PRCA)

Clinical course depends on


( ) ( Dose dependent) () precursor ** ADR ADR ** **

Drug induced Anemia 4 type


1. Impaired erythropoiesis related anemia 2. Anemia due to impair erythropoiesis 3. Megaloblastic anemia 4. Hemolytic anemia

Impaired erythropoiesis related anemia Incidence , onset, severity Clinical feature *Hb,Hct +/- abnormal RBC indices *blood smear:less RBC +/- abnormal morphology (microcytic, microchromic,anisocytic)

Management
Hb < 10 gm/dl Hypoxia Erythropoietin

Drug induced Megaloblastic anemia


Megaloblastic anemia ( ) 1. DNA & RNA 2. Vit B12 & Folic 1.Antimetabolites chemotherapy: MTX, 5-FU 2.Sulfa & Trimethoprim ** HIV 3.Anticonvulsant: Phenytoin, Barbiturate, Clinical feature Incidence , onset, severity Pale, Blood smear: large RBC, Polynucleated PMN RBC indices:MCV > 115-120 fl ,BMA:large megaloblast Vit B12& Folic

Management
folic Severe or High risk case Folinic acid or rescuvolin

Mild to Moderate anemia Folic acid **Concern D/I Vit B 12


Vit B 12 supplement 1-2 dose

Drug induced Methemoglobin anemia


Hb-Fe2+ Hb-Fe3+ (Methemoglobin)
Oxidant Drug
Antimalarial Drug Benzocaine Tissue Hypoxia

Serum methemoglobin >10%


Anemia/Cyanosis

Clofazimine
Dapsone Paraquat Phenazopyridine High dose Sulfa Nitrate/Nitrite

Management
Methylene blue 1-2 mg/kg over 5 min

If G6PDHemolytic ***

Drug induced Hemolytic anemia


Metabolic type Hemolytic anemia Immune type Hemolytic anemia

Drug increase risk of hemolysis individual with heredity RBC defect :


G6PD

Drug induce antibody against RBC

Peripheral RBC destruction

Drug induced Hemological defect in G6PD


Clinical feature RBC count,Hb.Hct

X-link gene disorder 10% in black American, Asians, Mediteraneans

Indirect billirubin, % reticulo count


Blood smear:usually normochromic anemia, poikilocytic,spherocy tic,

G6PD Def. Low Antioxidant Increase Methemoglobin RBC


Severity depends on

1. 2.

Dark urine
RBC

3. G6PD deficiency level 4

Metabolic type Hemolytic anemia

G6PD Deficiency

Drugs Able to Induce Hemolysis in G6PD-Deficient Patients pentose phosphate pathway

Drug induced Immune type Hemolytic anemia


High affinity hapten type [Drug-moiety on RBC]-Ab to RBC
(eg. High dose penicillin,tetracycline, tolbutamide)
Slow onset moderate- severe Hemolytic

Innocent bystander reaction [Drug-Ab]-RBC


(eg.2nd 3rd Ceph.)

sudden onset
severe Hemolytic+/- renal fail.

Ag-Ab Immune cpx.


Auto against RBC (eg. Cefotetan,
ceftriaxone)

Clinical feature +/- +/- Dark urine RBC count ,Hb.Hct Indirect billirubin,% reticulo count

Immune type Hemolytic anemia

Blood smear: normochromic anemia,poikilocytic,spherocytic,

Management

G6PD def. Immune type Hemolytic anemia rechallenge PRC Hb Active renal failure steriod Autoimmune

Drug induced Neutropenia or Agranulocytosis


Leukopenia = WBC < 3000/l Granulocytopenia =granulocyte<1500/l Neutopenia =ANC< 1500/l Agraulocytosis =ANC < 500/l

Rapid onset (2-14 day) in direct toxic or hypersens


Delay onset in Immune type()
Drug attack peripherally mature myeloid
Hypersens Immun mediated reaction

Mech.

Clinical Features Infection WBC, %N

ANC = WBC [%N+%band]


(if band cell >= 10%) ANC = WBC *%N (if band cell <10%)

management

Drug induced Thrombocytopenia


Impair coagulation Anticoagulant
Mech. 1.Direct toxic to thrombopoiesis/ peripheral platelet 2.Immunoreaction to peripheral platelet Hapten-type Rx(Heparin, abciximab) Innocent bystander type (quinidine high dose) Drugs induced Ab against platelet **Other factors: heavy alcohol,hepatic disease Clinical Feature
Plt.count < 100,000/l
(normal:150,000-300,000/l)

If < 50,000 spontanous bleeding Sign of Impair coagulation (petechia,bruisebleeding)

management ( immune ) rechallenge(immune) IM,SCbleeding

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

Heparin induced Dual Thrombocytopenia /Embolism


Platelet-Heparin-PF4 + IgG
Incidence 75-88%

Immune complex-Platelet

Platelet-Heparin-PF4 IgG
Splenic macrophages

Thrombocytopenia

Thrombosis
Stroke, arterial occlusion*
*HEP treatment failure ?

Thrombocytopenia LMWH induced Thrombocytopenia


Incidence < Heparin Mech:~ HIT

LMWH: Not recommend to use alternative in pt. HIT

Abciximab 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

Drug Induced Thrombotic Thrombocytopenic Purpura (TTP)


5 Cardinal Features Thrombocytopenia

Microangiopathic hemolytic anemia RBC fragment & organlesion


Neurological changes Progressive renal failure
Incidence 3.7 cases/1 million/year
Mortality rate 10-20% Onset < 1 mo. (not relate to pre-treatment plt.level)

Fever

Drug induced TTP management Ticlopidine/ Clopidogrel Penicillin plasma recovery Some antineoplastics Oral contraceptive drugs

Drug Induced Aplastic anemia


BM suppression rapid & seriously impair hematopoiesis
Cardinal feature = 2 from 3 defects with BM aplasia Clinical feature Sign & symptom of anemia,granulocytopenia,th rombocytopenia 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
WBC <3,000, Plt. <50,000 Hb<10 g/dl, Reticulocyte<30,000

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)

Drug Induced Aplastic anemia


management

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

Drug induced Pure Red Cell Aplasia (PRCA)


PRCA = Anemia that affect only erythroid cell line
Condition induce PRCA
Autoimmune disease.

Drug induce PRCA


Immunosupressive ag.

Viral infection:Hepatitis B, Parvovirus B19


Immunocompromise status

Antiviral drugs
Anti-infective ag. Anticonvulsants Drug related to Folic acid def. Erythropoetin like products: EPO> Other:Alloprinol, -methyldopa

Post-transplantation
Neoplasm:Thymus carcinoma, B-LL

Folic acid Def.


PRCA inheritant

Drug induced Pure Red Cell Aplasia (PRCA)


Clinical feature Reduction of RBC count ,Hb, Hct, reticulocyte count < 1% +/- moderate granulocytopenia or thrombocytopenia Normal or Low billirubin Blood smear: less cells may be small BM aspirate: hypocellular erythroid cells
Mech.

Hypersensitivity Direct toxic to erythroid cell line Immune induction Immune cpx.of drug/metabolite(eg.EPO Hapten (eg.diphenylhydantoin) *may be Folic def. to induce aplastic crisis

management

Blood cell supplement maintain O2 supply

( )

Drug induced renal and Liver disorder are coming soon ^^