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Choice and Monitoring of drug therapy - Dr Ashish Bavdekar
- 1. Chairpersons: Aabha Nagral, Prashanth LK,SK Yachha Talk: Ashish Bavdekar Choice and Monitoring of Drug therapy
- 2. Wilson’s Disease – choice and monitoring of drug therapy Dr. Ashish Bavdekar Associate Professor Consultant Ped. Gastroenterologist K.E.M. Hospital, Pune bavdekar@vsnl.com
- 3. Wilson’s Disease - therapy 1) Reduce Cu to sub-toxic threshold - takes 6-12 months - DP, Trientine, TAM 2) Maintain slightly negative Cu balance - life long therapy - DP, Trientine, Zn
- 4. Zn + penicillamine Zn + trientine Zn sulfate Zn acetate trientine penicillamine transplanted EuroWilson: initial treatment Why? “Available in our country Cheap Tried and tested What we’ve always used “Not available in our country Kept as second line Not as effective? “expensive”
- 5. Treatment depending on severity acute liver failure with encephalopathy acute liver failure without encephalopathy intermediate severity Asymptomatic transaminitis Asymptomatic and normal LFTs Neonate detected by screening Tx DP/Trientine + zinc ‘bridge’ Modified Kings score Tx if >11 DP/Trientine + zinc
- 6. Score Bilirubin mol/Lɥ INR AST IU/L WCC x 109 /L Albumin g/L 0 0-100 0-1.29 0-100 0-6.7 >45 1 101-150 1.3-1.6 101-150 6.8-8.3 34-44 2 151-200 1.7-1.9 151-300 8.4-10.3 25-33 3 201-300 2.0-2.4 301-400 10.4-15.3 21-24 4 >301 >2.5 >401 >15.4 <20 Modified King’s score A score > 11 = urgent need for transplantation Validated in other centres; better than PELD Dhawan et al, 2005
- 7. acute liver failure with encephalopathy acute liver failure without encephalopathy intermediate severity Asymptomatic transaminitis Asymptomatic and normal LFTs Neonate detected by screening Tx DP/Trientine + zinc ‘bridge’ Modified Kings score Tx if >11 DP/Trientine + zinc Zinc Zinc – when to start? Treatment depending on severity
- 8. acute liver failure with encephalopathy acute liver failure without encephalopathy intermediate severity Asymptomatic transaminitis Asymptomatic and normal LFTs Neonate detected by screening List for Tx DP/Trientine + zinc ‘bridge’ Modified Kings score Tx if >11 DP/Trientine + zinc Zinc Zinc – when to start? Treatment depending on severity
- 9. DP Trientine Zinc Chelator Chelator Induces MT Easy availability Patient named basis Easy availability Reasonable cost Rs. 1500/month V. Expensive Rs. 30,000/month Cheap Rs. 400/month Side effects +++ Minimal SE Gastric discomfort All except V. severe t-penia DP intolerance Neurological (?) Initial co-Rx Presympt. Cases Maintenance Rx
- 10. DP Trientine Zinc Chelator Chelator Induces MT Easy availability Patient named basis Easy availability Reasonable cost Rs. 1500/month V. Expensive Rs. 30,000/month Cheap Rs. 400/month Side effects +++ Minimal SE Gastric discomfort All except V. severe t-penia Significant renal D DP intolerance Neurological Initial co-Rx Presympt. Cases Maintenance Rx
- 11. Monitoring in WD ? • To determine clinical and biochemical improvement/deterioration • Determine effective decoppering • Ensure compliance • To identify adverse effects of medications • To review diagnosis if necessary
- 12. Monitoring plan (chelators) • Clinical – Liver status, neuro-psychiatric worsening – KF ring annually • Biochemical (USG) – CBC, Urine, LFTs – Initially 5, 10, 15, 30 days initially – Later 3 mo, 6mo, • Urinary Cu, Serum free copper (Serum Cu & Cp) – Initially after a month, 4 times per year – Later 1-2 times per year
- 13. Monitoring plan (chelators) • Clinical – Liver status, look for side effects – KF ring annually • Biochemical (USG) – CBC, Urine, LFTs – Initially 5, 10, 15, 30 days initially – Later 3 mo, 6mo, • Urinary Cu, Serum free copper (Serum Cu & Cp) – Initially after a month, 4 times per year – Later 1-2 times per year
- 14. DP Trientine Zinc Early (1-3wks) Fever, Rash Neutropenia, Thrombo, Proteinuria, Lnpathy Neurolog deterioration Avoid iron + T Rashes Haem. Gastritis Sideroblastic A Loss of taste Gastritis Leucopenia Increased lipase and amylase Late Nephrotoxicity Lupus like S Skin – EPS, pemphigus, lichen planus, V Late Myasthenia, Polymyositis Retinitis
- 15. Monitoring plan (chelators) • Clinical – Liver status, neuro-psychiatric worsening – KF ring annually • Biochemical (USG) – CBC, Urine, LFTs – Initially 5, 10, 15, 30 days initially – Later 3 mo, 6mo, • Urinary Cu, Serum free copper (Serum Cu & Cp) – Initially after a month, 4 times per year – Later 1-2 times per year
- 16. Biochemical improvement • Children on long-term chelation – 20/32 children normalised at variable times – INR - median of 1.8 yrs (0-12.2) – AST – median of 0.97 yrs (0-9) – Bilirubin – median of 0. yrs (0-2.3) • Asymptomatic sibs – 15/17 normalised LFTs – Median 283 days (35days-6.7yrs) Dhawan et al, 2005
- 17. Monitoring plan (chelators) • Clinical – Liver status, neuro-psychiatric worsening – KF ring annually • Biochemical (USG) – CBC, Urine, LFTs – Initially 5, 10, 15, 30 days initially – Later 3 mo, 6mo, • Urinary Cu, S. free copper (Serum Cu & Cp) – Initially after a month, 4 times per year – Later 1-2 times per year
- 18. Zinc DP / Trientine Initial Rx U Cu 100-500 ug/d S free Cu > 25 ug/dL U Cu > 500ug/d S free Cu > 25 ug/dL Good control U Cu < 75ug/d S free Cu 10-15 ug/dL U Cu 200-500 ug/d U Cu < 100 ug/d 48hrs after stopping DP S free Cu 10-15ug/dL Non-compliance/ Inadequate dose U Zn < 2mg/d U Cu < 200 ug/d U Cu > 500 ug/d S free Cu > 15ug/dL Over-treatment U Cu < 25 ug/d S. free Cu < 5 ug/dL Anemia, leucopenia Increased ferritin U Cu < 200 ug/d S. free Cu < 5 ug/dL Anemia, leucopenia Increased ferritin Urinary copper in Wilson’s disease
- 19. Zinc DP / Trientine Initial Rx U Cu 100-500 ug/d S free Cu > 25 ug/dL U Cu > 500ug/d S free Cu > 25 ug/dL Good control U Cu < 75ug/d S free Cu 10-15 ug/dL U Cu 200-500 ug/d U Cu < 100 ug/d 48hrs after stopping DP S free Cu 10-15ug/dL Non-compliance/ Inadequate dose U Zn < 2mg/d S free Cu > 15ug/dL U Cu < 200 ug/d U Cu > 500 ug/d S free Cu > 15ug/dL Over-treatment U Cu < 25 ug/d S. free Cu < 5 ug/dL Anemia, leucopenia Increased ferritin U Cu < 200 ug/d S. free Cu < 5 ug/dL Anemia, leucopenia Increased ferritin Urinary copper / serum ‘free’ copper
- 20. Summary • Chelators - mainstay of treatment (hepatic) • Zinc has role in long-term Rx, neurological, co-Rx • Monitoring is crucial – Clinical and improvement in LFTs slow • Monitoring for Cu balance important – Interpretation important – Compliance
Editor's Notes
- Outcomes diffciult to compare – no head tp head study, results vary accoding to system involved, severity, compliance, age
- ALF with E – may not help in RF ALF without E – Kings score – 93% sen 98% spe, some have found it to be less accurate CLD – imperfect evidence, local protocols rather that EBM, in a recent series, 40% patients had 1 change and 11% 2 changes in treatment. In a review of 288 patients with a median follow-up time of 17.1 years, Weiss et al (2011) concluded that hepatic treatment failure, defined as an increase in activity of liver enzymes occurred more frequently from zinc therapy (14/88 treatments) than from chelator therapy (4/313 treatments; P &lt; .001). Actuarial survival, without transplantation, showed an advantage for chelating agents (P &lt; .001 vs zinc). Patients who did not respond to zinc therapy showed hepatic improvement after reintroduction of a chelating agent. Neonate Because of the risk of copper deficiency, it should not be in the first year. Because clinical presentation is rare below 3 years, commencement at the age of 2 years is a defensible, if not wholly evidence-based, decision.
- Single dose trientine – 15mg/kg, 8 adult pts
- Single dose trientine – 15mg/kg, 8 adult pts
- DP may need to stopped in approx 30% cases Give with food to ensure compliance.
- Improvent is important
- Ucu &lt; 100 after 2 days of stopping DP – good terapeutic effect, &gt;100 non compliance To document therapeutic efficiency, urinary copper excretion after 2 days of D-penicillamine cessation should be &lt; 100. If more , suggest poor compliance Accurate measurement important
- Ucu &lt; 100 after 2 days of stopping DP – good terapeutic effect, &gt;100 non compliance To document therapeutic efficiency, urinary copper excretion after 2 days of D-penicillamine cessation should be &lt; 100. If more , suggest poor compliance