Drug a nd Herbal Induced - PowerPoint Presentation

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Drug and Herbal Induced NephrotoxicitySayamon Sukkha Pharm.D.Faculty of Pharmacy, Mahidol University22 January 2017

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Outline

Introduction to drug induced nephrotoxicityCase studyHerbal induced nephrotoxicity

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Clinical presentation of DIKD

Acute kidney injury (AKI)Chronic kidney disease (CKD)Nephrotic syndromeElectrolyte and acid base abnormalities

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Renal structural-functional alteration

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Pre-renal impairment

Intrinsic-renal impairment

post-renal impairment

Glomerular injury

Tubulointerstitial

Tubular obstruction

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Hemodynamic-mediated kidney injury

ACEIs/ARBsNSAIDsTubular epithelial cell damageAcute tubular necrosisAMGsAmphotericin BCisplatinRadiocontrast agentsOsmotic nephrosis

Glomerular diseaseTubulointerstitial disease: AIN, CINObstructive nephropathyIntratubular obstruction, neprholithiasis, nephrocalcinosisRenal vasculitis, thrombosis, and cholesterol emboli

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EXAMPLES

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กรณีศึกษา

ผู้ป่วยหญิงไทย อายุ 81 ปีCC : เหนื่อยมากขึ้น 1 ชั่วโมง ก่อนมาร.พ.PI: 2 เดือนก่อนมาร.พ. มีอาการปวดเมื่อยตามตัว ซื้อยาสมุนไพร และยาชุดมาทาน ปัสสาวะออกดี ทานยารักษาโรคประจำตัวอยู่เดิม ไม่เคยขาดยา 2 วันก่อนมาร.พ. ญาติเริ่มสังเกต เริ่มมีปัสสาวะออก น้อยลง ปัสสาวะไม่แสบขัด ทานได้ปกติ ไม่มีถ่ายเหลว 1 วันก่อนมาร.พ. นอนหายใจเหนื่อย ปัสสาวะไม่ออก

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กรณีศึกษา (2)

PMH: ความดันโลหิตสูง Type 2 DMโรคไตเรื้อรัง baseline Scr = 1.31 mg/dL (11/7/59)  eGFR = 38 mL/min/1.73 m2 stage 3AMH:Prazosin (1) 1x1 po pc Metformin (500) 1x1 po pcAtenolol (50) 1x1 po pc Folic acid (5) 1x1 po pcAmlodipine (10) 1x1 po pc Bisacodyl 1 tab po hsEnalapril (20) 1x1 po pc Gemfibrozil (600) 1x1 po ac

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กรณีศึกษา (3)

At ER:V/S: BT = 37.9° C HR 70/min BP 110/70 mmHg RR 36/minOn ET tubeDTX 495 mg/dLArterial blood gas (ABG) after ET-tube: pH 6.3, PCO2 17 mmHg, Lactate 12.5 mmol/LEKG 12 lead: sine wave, wide QRS complex

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กรณีศึกษา (4)

CBC: Hb 10.9 g/dL Hct 36 % Platelet 236,000 WBC 17,200 neutrophil 77%Electrolyte: Na 132 mEq/L K 9.12 mEq/L Cl 101 mEq/L HCO3 < 5 mEq/LRenal function: BUN 121 mg/dL Scr 8.5 mg/dLRx. 10% Calcium gluconate 4 ampRI 10 U IV drip 7.5% NaHCO3 8 amp + D5W iv drip

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Problem list

Severe metabolic acidosis Acute kidney injurySevere hyperkalemia

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Medication reconciliation

ซักถามประวัติยา/สมุนไพร เพิ่มเติมจากผู้ป่วยญาติให้ข้อมูลว่ากินยาสมุนไพรหมอชูกินครั้งละ 1 ซอง วันละ 2 – 3 ครั้งติดต่อกันเป็นเวลา 2 เดือน

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ยาสมุนไพรหมอชู

รักษาโรคปวดข้อ ปวดเส้น กระดูกทับเส้น ภูมิแพ้ ไซนัส โรคหอบหืด ยาเม็ดลูกกลอน จัดเป็นชุดๆ ละ 5 เม็ด มี 3 สี คือ สีแดง 2 เม็ด: Dexamethasone, Diclofenac, Vitamin B1สีน้ำตาล 2 เม็ด : Dexamethasone, Diclofenac, Vitamin B1สีดำ 1 เม็ด : Diclofenacและประกอบด้วยยาสมุนไพร อีก 9 ชนิดเช่น เหงือกปลาหมอ พริกไทย หญ้าหนวดแมว

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NSAID induced AKI

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Glomerular regulation

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Drugs that alter renal hemodynamics

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GFR

Scr

, BUN

Urine output

Volume overload, hypertension

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NSAIDs and COX enzymes activity

Expert

Opin Drug Saf. 2009 Nov;8(6):669-81.

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J Pain Symptom Manage.

 2003 Feb;25(2 Suppl):S41-9.

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Distribution of COX-1 and COX-2 in the human kidney

Role of PG in the kidney

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NSAIDs and the kidney: various clinical presentation

Pre-renal azotemiaHemodynamic-mediated kidney injuryAKIHyperkalemiaNa retention**Edema

ATNAINNephrotic syndromeAnalgesic nephropathy

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NSAIDs and the kidney

The risk of nephrotoxicity should be cautious both traditional NSAIDs and coxibsPatients at risk for nephrotoxicity: volume depletion, renal insufficiency, elderlyPatients with CrCL less than 30 mL/min should NOT be treated with NSAIDsThe renal side effect appear to be dose-dependent and related with chronic exposure

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Metabolic acidosis

(suspected from metformin)

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Metformin and lactic acidosis

Rare, lactic acidosis may also occur after overdose or with therapeutic use of metformin in normal renal functionThe incidence of lactic acidosis is approximately 0.015 fatal cases/1,000 patient-years, it is fatal about 50% of casesLactic acidosis may also occur in association with a number of pathophysiologic conditions

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Risk factors for lactic acidosis with MFM

Age of >60 yrDecreased cardiac, hepatic, or renal functionDiabetic ketoacidosisSurgeryRespiratory failureEthanol intoxication

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Dosage recommendation of Metformin

Guidelines Dose recommendation in CKDCombined ADA/EASD 2012-Safe is GFR < 30 mL/min/1.73 m2-Consider a dose reduction when eGFR 45 mL/min/1.73 m2NKF-KDOQI guidelines-Re-evaluate use when GFR < 45 mL/min/1.73 m2-Stop use when < 30 mL/min/1.73 m2AACE/ACE 2015 guidelines-Contraindicated in stage 3B, 4, or 5 CKDCDA guidelines -Reduce dosage if eGFR 30-59 mL/min-Use alternative agent if eGFR < 30 mL/min/1.73 m2

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The labeling recommendations

Before starting metformin, obtain the patient’s eGFRMetformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m2Starting metformin in patients with an eGFR between 30-45 mL/min/1.73 m2 is not recommendedObtain an eGFR at least annually in all patients taking metformin

http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm (Update 4/8/2016)

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Primary care with a patient safety approach

Am J Kidney Dis.

 2009 Apr;53(4):681-8.

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Ideal patients with CKD with following time-course detection

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Herbal

induced nephrotoxicity

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สมุนไพรรักษาอาการขัดเบาในระบบทางเดินปัสสาวะ: กระเจี๊ยบแดง ขลู่ ตะไคร้ สับปะรด หญ้าหนวดแมว

กรมพัฒนาการแพทย์แผนไทยและการแพทย์ทางเลือก: สมุนไพรในงานสาธารณสุขมูลฐาน. Available at: http://www.dtam.moph.go.th/indigenous/index.htm

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สมุนไพรในสาธารณสุขมูลฐาน

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Brief description:

Chinese

slimming herbal

remediesToxic substances: Aristolochic acidClinical presentation:Chronic interstitial nephritisRenal tubular defectsUrothelial malignancies

Aristolochic

fangchi

กระเช้าสีดา ไก่ฟ้า พญาลอ

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Prevalence of herbal and dietary supplement (HDS) usage in Thai CKD

The prevalence of HDS use among Thai CKD patients was 45%HDS use in CKD patient was greater than general population (33%) (Ingsathit A, 2010)HDS users were more likely to have poor medication adherence than non-users (p = 0.015)

BMC Complement Altern Med. 2013 Jul 1;13:153.

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Disclosure of HDS use to doctors and the reasons for NOT disclosing (n = 189)

BMC Complement

Altern Med. 2013 Jul 1;13:153.

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Herbs used reports in Thai CKD patients

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Type of

Herb used Frequency (%) Main purposed given by respondentsAEs experienceKariyat (ฟ้าทะลายโจร)11Common cold, fever, sore throat, diabetesIncreased ScrTurmeric (ขมิ้นชัน)9.5GI symptoms, constipation, CKD-Horseradish tree (มะรุม)8DM, HTN, constipationUnable to stop bleedingMixed botanical extract or fruit drink6CKD, DM, well-being-Ginseng (โสม)3.5Well-being-Holy mushroom (เห็ดหลินจือ)2.5CKDEdema River spiderwort (หญ้าไผ่น้ำ)2CKDIncreased in Scr, fatigue

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Why do Thai patients with CKD use or not use herbal and dietary supplement ?

A prospective, cross-sectional study in 421 patients with stage 3-5 CKD in Thailand.Patients were interviewed at baseline regarding their HDS use, information sources, and reasons for HDS use or non-use.

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Reasons why HDS used (n = 271)

BMC Complement

Altern Med. 2014 Dec 6;14:473.

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Reasons why patients decided to use or stop using HDS at the end point (n = 357)

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to use HDS (n = 123)Gaining benefit from using HDS73 (59)Expecting to gain benefit32 (26)To supplement their diet8 (6)Their family members or friends provided HDS6 (5)Recommended by their doctor2 (2)Used to take it1 (1)HDS is safe1 (1)

Stopping

HDS use (n = 43)

Recommended by their

doctor

10 (23)

Having

AE from using HDS

8 (19)

Their

minor ailments relieved

8 (19)

Do not

want to use

5 (11)

Experience with no benefit from using HDS

3 (7)

Concern about AE on the kidney

3 (7)

Cannot afford or available

3 (7)

Receiving dialysis or their

disease worsened

2 (5)

Taking high numbers

of conventional medicines

1 (2)

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Nephrology (Carlton).

 2015 Jun 4.

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DEF

: progression to CKD

Change in

eGFR

> 5 mL/min/1.73 m

2

or

go on RRT

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The results: HDS and the progression to CKD

No association between HDS and the progression of CKD over a one-year period (adjusted OR 1.16, 95% CI 0.66-2.03)Two patients had AKI, which may be related to an unknown Chinese herbal medicine, or river spiderwort combined with diclofenac reported in the medical notesThe use of HDS was associated with uncontrolled hyperphosphatemia (adjusted OR 3.53, 95% CI 1.20-10.43)

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NameFrequency (%)NameFrequency (%)Fish oil7Calcium supplement2Protein supplement7Vitamin B2Germ oil6Beta-glucan1Essence of chicken drink5Bee pollen1Rice bran oil5Chlorophyll 1Vitamin C5Cod liver oil1Gingko4Chondroitin 1Multiple vitamin 3CoQ101Swiftlet’s nest drink3Glucosamine 1Vitamin E3Omega-31Wheatgrass 3Lecithin 1Virgin cold pressed coconut oil2Zinc 1A product contained vitamins, mineral and botanical extracts3A product contained vitamins, minerals and cereal1

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High Phosphate

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HDS was reported to be harmful the kidney (1)

River spiderwort หญ้าไผ่น้ำ Kariyat ฟ้าทลายโจรWheatgrass วีทกราสThai herbal medicine containing aloe (ว่านหางจรเข้) for laxative AKI (Luyckx VA, 2002)Thai traditional medicine for cancer called “Luke Klon” (ลูกกลอน)  may contain steroid that can cause AKI

BMC Complement Altern Med. 2014 Dec 6;14:473.

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HDS was reported to be harmful the kidney (2)

Protein supplement proteinuriaNo scientific evidence to maintaining kidney functionพุทราอินเดีย กระชาย อัญชัน ฟักข้าว ปอกะบิด

BMC Complement Altern Med. 2014 Dec 6;14:473.

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HDS that have studies to prove the effect in kidney

HDS that has an evidence to inhibit angiotensin converting enzyme in vitro studies กระเจี๊ยบแดง ถังเช่า ขิง หอมแดง มะรุม ใบบัวบก (Ojeda D, 2010, Shashidhar MG, 2013, Somanadhan B, 1999, Hansen K, 1995)HDS that were reported by responders for anti-hypertensive effect มะรุม บัวบก

BMC Complement Altern Med. 2014 Dec 6;14:473.

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Take home message

Principles for prevention of DIKDTo avoid the use of nephrotoxic agents and avoid combination of DIKDAdjustment of medication dosage regimen based on renal functionFamily and friends influence patient’s decision-making regarding HDS use amongst Thai peopleProfessionals should ask about patient’s use of HDS and monitor the impact of HDS on CKD patients

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