This is my 35th powerpoint..published here in Google Slideshare... And I wish to thank everyone who have supported me in my 2 year long journey...... This ppt is regarding DRUG INDUCED HEMATOLOGICAL DISORDERS, covering the definitions, causative drugs, pathophysiological mechanisms, manifestations,and management of 5 blood disorders. Do go through this ppt, and send me ur reviews!! Regards, Vishnu.R.Nair.

1. DRUG-INDUCED
HEMATOLOGICAL
DISORDERS: A PRECISE
INSIGHT
PRESENTED BY:
VISHNU.R.NAIR,
FIFTH YEAR PHARM.D,
NATIONAL COLLEGE OF PHARMACY, KERALA
EMAIL ID: rxvichu623@gmail.com

2. A. DEFINITION:
• “Rare, adverse hematological events, associated with drug therapy”.

3. B. TYPES :
Include:
1. APLASTIC ANEMIA
2. AGRANULOCYTOSIS
3. HEMOLYTIC ANEMIA
4. MEGALOBLASTIC ANEMIA
5. THROMBOCYTOPENIA.

4. DRUG-INDUCED APLASTIC
ANEMIA

5. 1. DEFINITION:
- “Condition, in which body is UNABLE to produce ENOUGH NEW BLOOD CELLS”
2. PATHOPHYSIOLOGY:
Drug-inducedAplastic Anemia can be caused by 3 mechanisms:
i. Direct, dose-related drug toxicity
ii. Idiosyncratic mechanisms
iii. Drug-induced autoimmune aplastic anemia.

6. i. DIRECT, DOSE-RELATED DRUGTOXICITY :
- Drug  causes transient bone-marrow failure , depending on dose escalation
- Caused by chemotherapy/ radiation therapy.
ii. IDIOSYNCRATIC MECHANISMS:
- Potentiality for toxicity increases with:
a. Toxic metabolite of parent drug
b. Pharmacokinetic variations among individuals, with respect to the affecting drug
c. Genetic polymorphisms  causes hypersensitivity of stem cells towards drug/ its
metabolites.
iii. DRUG-INDUCED IMMUNE APLASTIC ANEMIA:
- Drug  activates cells & cytokines of immune system  causes stem cell destruction.

7. 3. CLINICAL MANIFESTATIONS:
- WBC count < 3,500 cells/cumm
- Low Hb count(<10 g/dL)
- Fatigue
- Fever
- Weakness
- Bleeding
- High propensity for infections.

8. 4. CAUSATIVE DRUGS:
Include:
- Aspirin
- Chloroquine
- Hydrochlorothiazide
- Chloramphenicol
- Chlorpromazine.

9. 5. MANAGEMENT:
- Early withdrawal of offending drug
- Supportive care
- Antibiotics(For infections, use BROAD-SPECTRUM ANTIBIOTICS)
- Transfusion(to supplement RBCs & PLATELETS)
- HSCT(Hematopoietic Stem CellTransplantation)
- IMMUNOSUPPRESSIVE THERAPY:
a. Usually combination of ATG(Antithymocyte Globulin) & CYCLOSPORINE is used
b. ATG is derived from horses/rabbits
c. ATG  consists of polyclonal IgG  directed againstT-CELLS
d. Dose of ATG : 40 mg/kg/day, for 4 days.

10. e. CYCLOSPORINE  blocks IL-2 production  reducesT-CELL activity
f. Dose of cyclosporine  5 mg/kg/day, in 2 divided doses.
- CORTICOSTEROIDS:
a. Mainly used to reduce the ADRs ofATG therapy
b. Drug/s used: METHYLPREDNISOLONE/ PREDNISOLONE  1 mg/kg/day, for 2-4 weeks.

11. DRUG-INDUCED
AGRANULOCYTOSIS

12. A. DEFINITION:
“Condition, in which there is a reduction in the number of MATURE MYELOID
CELLS(Granulocytes & immature ones) in the body, to a total count of 500 cells/mm3, or
less.”
B. PATHOPHYSIOLOGY:
OCCURS BY 4 MECHANISMS:
1. HAPTEN MECHANISM:
- Drug / metabolite  binds to surfaces of neutrophils  forms a complex  complex acts
as “HAPTEN”  Stimulates ANTIBODY PRODUCTION  Antibodies bind to complex 
destruction of neutrophils, via complement & phagocytic systems.
- Caused by high, repeated doses of PENICILLIN.

13. 2. INNOCENT BYSTANDER PHENOMENON:
- Drug  binds to drug-specific antibody  forms complex This complex binds/ adsorbs
non-specifically to neutrophil membrane  induces antibody production  destruction of
neutrophils, via complement & phagocytic systems.
- Caused by QUINIDINE.
3. PROTEIN-CARRIER MECHANISM:
- Drug  binds to protein carrier forms complex  this complex adsorbs to neutrophil
surface  induces antibody production  destruction of neutrophils.
4. PRODUCTION OF AUTOANTIBODIES TO SPOILT MEMBRANE:
- Drug  alters structure of neutrophil membrane  induces formation of autoantibodies 
auto-antibodies bind to neutrophils  destruction of neutrophils, via phagocytosis.

14. 3. SIGNS & SYMPTOMS:
- Chills
- Malaise
- Increased propensity towards infections
- Sore throat
- Fever
4. CAUSATIVE DRUGS:
Drugs, that causeAGRANULOCYTOSIS include:
a. Ampicillin
b. Chloramphenicol
c. HCQ

15. d. Gentamicin
e. Captopril
f. Quinine .
5. MANAGEMENT:
- Remove offending drug
- Treat infections with antibiotics
- Vigilant hygiene practices
- FILGRASTIM(300 mcg/day; s.c) , SARGRAMOSTIM {Only if NEUTROPHIL COUNT<100
cells/mm3}.

16. DRUG-INDUCED HEMOLYTIC
ANEMIA

17. A. DEFINITION:
“Process of premature RBC destruction, in which RBCs are destroyed at a rate, faster than
bone marrow can replace them.”
B. PATHOPHYSIOLOGY:
Caused by 4 mechanisms, under 2 broad headings:
DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA:
1. HAPTEN MECHANISM:
- Caused by :
• Penicillin
• Cephalosporins
• Streptomycin.

18. 2. INNOCENT BYSTANDER PHENOMENON:
- Caused by:
• Sulfonamides
• Quinine
• Quinidine
3. DRUG-INDUCED AUTOIMMUNE HEMOLYTIC ANEMIA:
- Drug  induces true auto-antibodies to RBCs

19. DRUG INDUCED OXIDATIVE HEMOLYTIC ANEMIA:
- Found in patients with G6PD, glutathione peroxidase deficiencies
- G6PD deficiency is a disorder of HMP SHUNT
- G6PD deficiency  causes lack of NADPH concentration in RBCs  reduces
GLUTATHIONE levels (in reduced form)  no substrate available for
glutathione peroxidase to bind on  reduces protective effect of glutathione
peroxidase on RBCs  PEROXIDES attack RBCs  oxidative stress  leads to
hemolysis
- With reduced glutathione levels  oxidizing drugs oxidize –SH group of
Hemoglobin  leads to PREMATURE RBC DESTRUCTION  leads to
HEMOLYSIS.

20. C. SIGNS & SYMPTOMS:
1. Pallor
2. Fatigue
3. SOB
4. Malaise.
D. CAUSATIVE DRUGS:
Drugs, that cause hemolytic anemia, include:
1. Metformin
2. NTU
3. Sulfacetamide
4. Sulfanilamide
5. Sulfamethoxazole.

21. E. MANAGEMENT:
1. TREATMENT OF DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA:
- Remove offending drug
- Supportive care
2.TREATMENT OF DRUG-INDUCED OXIDATIVE HEMOLYTIC ANEMIA:
- Remove offending drug.

22. DRUG-INDUCED
MEGALOBLASTIC ANEMIA

23. 1. DEFINITION:
“Condition, in which there is abnormal development of RBC PRECURSORS(Megaloblasts), in
bone marrow”.
2. PATHOPHYSIOLOGY:
- VITAMIN B12, FOLATE DEFICIENCY  causes impaired proliferation & maturation of
hematopoietic cells  causes cell-cycle death, with subsequent sequestration.
- Drugs(Methotrexate, co-trimoxazole)  block DHFRase  Deoxy-thymidine triphosphate
is not formed  DNA synthesis doesn’t occur.
- Since CO-TRIMOXAZOLE is LESS-SPECIFIC to human DHFRase  disease occurs ONLY IN
THOSE,WITH VITAMIN B12/ FOLATE DEFICIENCIES.
- ANTI-EPILEPTIC DRUGS(Phenobarbital, primidone, phenytoin)  cause disease in 2 ways:
a. Blockage of folate metabolism
b. Increased folate catabolism.

24. 3. SIGNS & SYMPTOMS:
a. SOB
b. Malaise
c. Muscle weakness
d. Irregular heartbeats
e. Dizziness.
4. MANAGEMENT:
- For CO-TRIMOXAZOLE induced anemia  FOLINIC ACID (5-10 mg), QID
- ForAED-induced anemia  FOLICACID, 1 mg/day (Check for effectiveness ofAED in
patients, after starting FOLICACIDTHERAPY).

25. DRUG-INDUCED
THROMBOCYTOPENIA

26. A. DEFINITION:
“Condition, in which platelet count goes below 1,00,000 cells/mm3.”
B. PATHOPHYSIOLOGY:
Caused by 3 mechanisms:
1. DIRECT TOXICITY REACTIONS:
- CHEMOTHERAPEUTIC AGENTS  suppress thrombopoiesis  causes reduction in no. of
megakaryocytes in bone marrow.
2. HAPTEN-TYPE IMMUNE REACTIONS:
- Drug  binds to platelet glycoproteins  forms complex  induces ANTIBODY
FORMATION  antibodies bind to platelet surface  destruction of platelets, by
COMPLEMENT & PHAGOCYTIC SYSTEMS.

27. - Caused by:
a. Quinidine
b. Quinine
c. Rifampin
d. Heparin
e. Gold salts
f. Sulfonamides
3. DRUG-INDUCED AUTOIMMUNE THROMBOCYTOPENIA:
- Drug  induces production of auto-antibodies  auto-antibodies bind to platelet
membrane  cause platelet destruction
- Caused by:
a. Gold salts b. Procainamide .

28. C. SIGNS & SYMPTOMS:
1. Petechiae
2. Ecchymoses
3. Increased bruising
4. Bleeding from mucous membranes
5. Severe purpura
6. Epistaxis.

29. D. MANAGEMENT:
- Remove offending drug
- Supportive treatment
- FOR HEPARIN-INDUCEDTHROMBOCYTOPENIA:
i. Remove/discontinue all sources of HEPARIN
ii. Focus on ALTERNATIVE ANTICOAGULATION
iii. Go for DIRECT THROMBIN INHIBITORS, like LEPIRUDIN, BIVALIRUDIN,
ARGATROBAN
iv. ARGATROBAN:
- Requires dosage adjustments in liver dysfunction
- Can be used in ESRD patients.

30. v. BIVALIRUDIN:
- Requires dosage adjustment in severe renal failure.
vi. LEPIRUDIN:
- Obtained from leeches
- Requires dosage adjustments in kidney dysfunction
- 30% of patients  when treated with LEPIRUDIN for 1st time  formed
ANTIBODIES  Thus, focus on ONLY ONE TREATMENT COURSE FOR
LEPIRUDIN.

31. C. REFERENCE/BIBLIOGRAPHY:
1. Johnston FD. Granulocytopenia following the administration of sulfanilamide
compounds. Lancet 1938;2:1004–1047.
2. van der Klauw MM, Goudsmit R, Halie MR, et al. A population-based case-cohort study of
drug-associated agranulocytosis. Arch Intern Med 1999;159:369–374.
3. Maluf EM, Pasquini R, Eluf JN, et al. Aplastic anemia in Brazil: incidence and risk factors.
Am J Hematol 2002;71:268–274.
4. ASHP guidelines on adverse drug reaction monitoring and reporting. American Society of
Hospital Pharmacy. Am J Health Syst Pharm 1995;52:417–419.
5. Brodsky RA, Jones RJ. Aplastic anaemia. Lancet 2005;365:1647–1656.
6. Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al.Treatment of aplastic anemia with
antilymphocyte globulin and methylprednisolone with or without cyclosporine.The
GermanAplastic Anemia Study Group. N Engl J Med 1991;324:1297–1304.

32. 7. Tabbara IA. Hemolytic anemias. Diagnosis and management. Med Clin North Am
1992;76:649–668.
8. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002;69:258–
271.
9. Scott JM, Weir DG. Drug-induced megaloblastic change. Clin Haematol 1980;9:587–606.
10. George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: a systematic
review of published case reports. Ann Intern Med 1998;129:886–890.

33. THANK YOU!!!!!!