CURICULUM VITAECURICULUM VITAE

A.Personal Data

Nama Lengkat/Gelar :Prof. dr. Hardi Darmawan, MPH&TM, FRSTM, DAFKTempat/Tanggal Lahir : Palembang, 24 November Alamat :Jl. Ismail Marzuki No. 220/4235, Kel. Sekip Jaya, PalembangPhone :0711-353 374Email :hardidar@gmail.com

B.Working ExperienceRS RK Charitas1.Ka. Lab. Klinik2.Ka. Bid. Diagnostik3.Direktur Penunjang Medik4.Direktur Kerja Sama Antar Instansi dan Hubungan Luar Negeri5.Direktur Keuangan, Logistik & SDM6.Direktur Utama

C.Education1.Fakultas Kedokteran Universitas Sriwijaya – Dokter Umum2.Tulane University, USA – Master of Public Health and Tropical Medicine3.London, United Kingdom – Fellow of The Royal Society of Tropical Medicine and Hygiene4.Kolegium Ikatan Ahli Ilmu Faal Bandung / FK Unpad – Ilmu Faal / Fisiologi5.Ikatan Dokter Indonesia – Ilmu Faal / Fisiologi

Defisiensi Mikronutrient Akibat Pemberian Obat-obatanJangka Panjang

Defisiensi Mikronutrient Akibat Pemberian Obat-obatanJangka Panjang

Disampaikan Oleh: Prof. dr. Hardi Darmawan, MPH&TM, FRSTM, AIFI.,M

Disampaikan dalam SEMINAR NASIONAL PERUMAHSAKITAN & RAPAT KERJA NASIONAL PERSI 26 Juli 2017

Topik yang jarang sekali dibicarakan/dipresentasikan (A Story Rarely Told)Topik yang jarang sekali dibicarakan/dipresentasikan (A Story Rarely Told)

Rumah Sakit RK. Charitas PalembangFakultas Kedokteran UNSRI Palembang

Objectives1. To review

micronutrient-drug interactions.

2. To increase awareness of micronutrient-drug interactions for patient safety and wellness.

“Nungcik” 35 Thn Cholesterol : 298 mg/dL

Triglyceride : 220 mg/dL

Berat Badan > 115 Kg

Tekanan Darah : 200/110 mmHg

Gula Darah Sewaktu : 180 mg/dL

GERD

Diet >

Sedentary

Merokok 3 bks / hari

Stress

Insomnia

kemana NUNGCIK mengarah ??

Latar Belakang

Physiology of DrugsPhysiology of NutrientPathophysiology of Drug Induced

Food-Nutrient Interaction Micronutrient Depletion

Drug-Nutrient Interaction Case StudiesKesimpulan

Prevalensi Mikronutrient DefisiensiEtiologyFaktor- faktor Resiko

Latar Belakang

• Vitamin dan Trace Elements adalah penting sekali untuk fungsi tubuh manusia

• Required Allowance – Food Intake• Deficiency Nutrients – Structural, Functional

Dysfunction

Supplementation

Reversible

Prevalence : Micronutrient Deficiencies Negara-Negara Industry 30% (1)

Prevalence : Micronutrient Deficiencies Negara-Negara Industry 30% (1)

Etiology: Deficiency Nutrient• Intake • Drug/Multiple drugs – nutrient interaction

– Lemah– Lansia -> 9-15 obat /h

• Prevalence zinc & selenium deficiency 50%

Resiko

Interaksi obat/makanan terhadap mikronutrient dipengaruhi faktor:•Umur•Gender•Riwayat Medis/Medical History•Komposisi Tubuh/Body Composition•Status Nutrisi/Nutritional Status•Jumlah obat yang digunakan

4 Tahap aksi obat yang dimakan ke dalam tubuh

Obat larut dalam bentuk

yang bisa diserap lambung

(usable)

Obat diabsorpsi ke dalam darah – transpor ke tempat aksi

Tubuh merespons

terhadap obat, berfungsi

sebagaimana mestinya

Ekskresi obat melalui:• Ginjal• Hati • Atau keduanya

Physiology of Drugs

• Tipe pengobatan• Bentuk obat: pil/tablet, cairan/sirup• Dosis• Tempat absorpsi : mulut, lambung, usus• Rute pemberian: oral, intravena, IV/Im, s.c

Pathophysiology of Drug/Food Induced

Efek Makanan/Obat terhadap Mikronutrient

3 Main Types of Drug Interactions

1.Drugs with food and beverages

3. Drugs with other drugs

2.Drugs with dietary supplements

Nutrient – Drug Interactions Nutrient – Drug Interactions Medications can affect nutrients by:

1. Decreasing food intake2. Decreasing nutrient absorption3. Slowing down nutrient production4. Interfering with nutrient metabolism5. Increasing nutrient excretion

Nutrient-Drugs Interactions

Nutriet - Drugs Interactions is a consequence of physical,chemical or pathophysiologic relationship between adrug and nutrient.

Interactions can occur between a drug and a nutrient,multiple nutrients, dietary pattern of spesific foods.

An interaction is clinically significant if it alters thetherapeutic drug response and/or compromisenutritional status.

Nutrient-Drugs Interactions

The interaction can therefore alter the therapeuticresponse.

• The interaction can result in decreased bioavailabilityof drug causing treatment failure or increasedbioavailability causing toxicity and adverse effects.

• The patient’s nutritional status and dietarycomponents with pharmacological activity can affectdrug metabolism thereby altering action and function.

Nutrient-Drugs Interactions

Drug can play a significant role in developing nutrientdeficiencies.

• Drug-induced micronutrient depletion may beresponsible for the unexplained symptoms that affectmedication compliance (zinc and ACE inhibitors andARAII).

Many micronutrients are potentially vulnerable to theeffects of prescribed medicines when consumption isregular and sustained.

Nutrient-Drugs Interactions

Vitamin and trace elements are essential to thebody

Micronutrients are required for intermediarymetabolism in varying amounts-usually < 1 gram/day toas low as a few micrograms/day

Nutrient-Drugs Interactions

Fruits, vegetables, herbs and teas contain a large varietyof micronutrients and phytochemicals that have beenassociated with health benerfits.

These however consist of complex phytochemicals thatcan inhibit or induce the activity of cytochrome (CYP)P450 family of enzymes

Common Interaction

Alkohol > 3x minum alkohol/hari

─ AcetaminophenSerious

Liver Damage

Alkohol > 3x minum alkohol/hari

+ NSAID

Perdarahan Lambung

Food-Nutrient Interaction

Buah-buahan, sayur-sayuran, herbal dan teh mengandung beberapa micronutrients – phytochemical yang baik untuk kesehatan.

Phytochemicals complex inhibitinduce Aktivitas CYP

(Cytochrome) P450enzyme

Food-Nutrient Interaction

Citrus Fruits Containing Furanocoumarins

• Grapefruit• Seville oranges• Limes• Pomelos

• Pomegranate – does not contain furanocoumarins but shares certain

chemical properties with grapefruit suggesting a potential drug

interaction

Grapefruit-Drug Interaction

Grapefruit juice does not need to be takensimultaneously with the medication in order to producethe interaction.

The bioavailability of drugs can be doubled bygrapefruit juice even several hours afteringestion

ACTION : Grapefruit and grapefruit juice shall not beincluded as patient menu selections

Chocolate

• The caffeine in chocolate can cause theeffects of stimulant medications (includingmethyl phenidate) to be intensified.

• Opposite effects with sedatives – can causetheir intended effects to be decreased.

• One ounce of dark chocolate can contain upto 35gm of caffeine, enough to potentiallycause a problem.

Chocolate

• Chocolate also contains tyramine, a chemicalthat controls blood pressure.

• If taking MAOI’s to treat depression, tyraminecan cause a dangerous increase in bloodpressure, potentially leading to a stroke.

Chocolate Caffeine di dalam chocolate stimulant medication

1 ons dark chocolate 35 gram caffeine problem prone

Methylphenidate

Chocolate mengandung Tyramine, chemical mengontrol tek. darah MAO inhibitor untuk terapi depresi

+ Tyramine tekanan darah ↑ Stroke

Licorice (glycyrrhizic acid) meningkatkan reabsorpsi sodium, water retention & meningkatkan tekanan darah

♀ 79 Th

Licorice (glycyrrhizic acid) increases sodium resorption,

water retention and increases blood pressure

BMJ Case Rep. 2012 Oct 19;2012. pii: bcr2012006805. doi: 10.1136/bcr-2012-006805.Kormann R1, Languille E, Amiot HM, Hertig A.Source Urgences Néphrologiques et Transplantion Rénale,APHP, Hôspital Tenon, paris, France

AbstractWe report the case of a 70-year-old woman who developed life-threatening arrhythmia as a result of acute and severe hypokalaemia, which she developed after consuming large quantities of a liquorice-rich herb tea. She had no previous heart condition. We also discuss the legislative discrepancy in both the USA and in Europe, whereby consumers are warned about the risk of chronic hypertension whenever they buy a product containing liquorice, yet the risk of hypokalaemia may not be mentioned at all.

Dying for a cup of tea.

Ginseng

Ginko Biloba

Interferensi the bleeding effect of coumadin

Bleeding effects of heparin, aspirin, NSAID

An convulsants ↓ control kejang ↓

Selected Drugs that Interact with Grapefruit & Other Fruits Containing Furanocoumarins

AntilipemicAgents

Cardiovascular agents

Atorvastatin,LovastatinSimvastatin

FelodipineNifedipineQuinidineVerapamilEplerenoneTicagrelor

AmiodaroneApixabanClopidogrelDronedaroneRivaroxabanQuinidine

Alternatives with the same therapeutic indication that have no or minor interaction

Pravastatin,RosuvastatinFluvastatin

AmlodipineAcetylsalicyclicWarfarin

SotalolSpironolactone

Cholesterol Lowering DrugsHmG-CoA ReductanInhibitors STATIN

Depleton Coenzyme Q10, Vit, D, Vit.E, Omega 3, Carnitine, Zinc, Selenium, Copper

Fibrates Depletes B12, E, Cu, Zn

Gemfibozil Depletes CoQ10, E

Bila acid sequent Deplete Vit. A, D, E, K, B12, Ca, Mg, P, Zn, Fe, folic acid, beta caraotene fat

HMG-CoAReductaseInhibitors(Statins)

Ubiquinone

STATINS

Coenzyme Q10

STATIN TESTOSTERONE ↓ (Giovanni Corona, MD)

CoQ10↓ • Obesity DM Type II• Myopathies• Muscle Fibers

Free Rad Res. 2002. 36(4). 445-453

• Obesity• Metabolic Syndrome• Insulin Resistance • Diabetes• CVD

Groosman J. Diri Endo. 2006

Sleep E. Leproult, 2011. JAMA

Early death of Heart disease Chris Malkin, 2010; Ronald. Heart, 2010

Anti Ulcer Drugs H2 Receptor antagonist : ↓B12, folic acid, Vit. D, Ca, Fe, Zn,

Protein PPI : Beta carotene, Ca, Vitamin D, B12, Mg, Protein

Odes, 1990Force & Nabate. Ann Rhesni. 1992 (26 – 1283 – 81)

Hydralazine : B6, CoQ10

Loop : Ca, Mg, K, Zn, B1, B6, C Thiazide : Mg, K, Zn, CoQ10

Beta Blocker : CoQ10, Melatonin

Anti Hypertensive Drugs

Potassium Sparing: Ca, Zn, FA

Clonidine/Methyldrope : CoQ10 ACE : Zn Chlorthalidone : Zn Goleb, Jan. 17-75-8 1998 Call nut

Magnesium and Loop Diuretics

Loop diuretics increase Mg excretion and inhibit passive Mg absorption

Quamme GA., “Renal magnesium handling: new insights in understanding oldproblem.” Kidney Int. 1997; 52(5):1180-95

Compare side effectrs of Thiazide Diuretics and Mg Depletion

Magnesium Depletion Thiazide Diuretic Side Effects

• Muscle cramps and spasms, including vasospasm

• Migraines• Anxiety, nervousness, and

insomnia• Low energy/fatigue• Increased BP• Arrythmia and heart

palpitations• Depression• Kidney Stones• Osteoporosis• Constipation• Blood Sugar disturbances

• Muscle pain, weakness or cramps

• Low back pain• Headache• Unusual tiredness or

weakness• Irregular heartbeat• Mood changes• Constipation• Glucose intolerance

• Source Facts & Comparisons

Magnesium Deficiency:Pathophysiologic and Clinical Review

• Cofactor for ATP, critical in energy production, protein synthesis and anaerobic phosphorylation

• If Mg is depleted, bone stores contribute to Extracellular Fluid

• “The serum Mg can be normal in the presence of intracellular Mg depletion, and the occurrence of a low serum level usually indicates significant Mg deficiency.”

Al-Ghamdi SM, Am J Kidney Diseasse. 1994 Nov; 24(5): 737-52

Magnesium

4637 Americans 18-30 free of MetS andDiabetes 15 year follow up 608 cases MetS.-Studies suggest magnesium intake may beinversely related to risk of hypertension and type2 diabetes mellitus:-Higher intake of magnesium may decreaseblood triglycerides and increase high-densitylipoprotein (HDL) cholesterol levels.

Circulation: Epidemiology: Magnesium Intake and Incidence of MetabolicSyndrome Among Young Adults 2006; 113: 1675-1682 Published online beforeprint March 27, 2006, doi:10.1161/CIRCULATIONAHA.105.588327

Magnesium cont’d

• Magnesium intake inversely related toindividual component of the metabolicsyndrome and fasting insulin levels.

• Conclusion― “Our findings suggest thatyoung adults with higher magnesium intakehave lower risk of development of metabolicsyndrome”.

MagnesiumMagnesium supplementation 500 mg elementalform for 4 wk in overweight individuals: distinctchanges in gene expression

Trial registered at clinicaltrials.gov as NCT00737815Magnesium Supplementation, metabolic and inflammatory markers, and globalgenomic and proteomic profiling: a randomized double-blind, controlled,crossover trial in overweight individuals Chacko, Sara, Sul, James, Song, Yiqinget al; Am J Clin Nutr February 2011 vol 93 no2 463-473

• C-peptide .4ng/ml• Insulin -2.2uU/ml• 24 gene up regulation and 36 down regulation• All related to metabolic and inflammatory pathways

Magnesium Status due to decrease Diatary intake or Altered metabolism

Magnesium Research. Volume 20, Number 2, 107-29, June 2007, Review articleDOI : 10.1684.mrh.2007.0096

Clotting• Pre-thrombotic stateInsulin resistance• Impaired glucose toleranceHypertension• Sm. Muscle contractility• Endothelial dysfunction• Aleration of response

angiotensin II, endothelin

Dyslipidemia• HDL LDL TG• HMGCoA• LDLInflammation• IL-1 IL-6 TNF-• AdiponectinOxidative Stress• Lipid oxidation• Vascular Remodeling• Endothelial dysfunction

Magnesium Intake and Risk of Type 2Diabetes in Men and Women

• 85,600 women and 42,872 men no Hxdiabetes CVD or cancer at baseline

• Magnesium Intake eval q2yr• 18 yr follow up women 4,085 cases• 12 year follow men 1,333 cases• Relative Risk 0,66 in women (P<0.001)• Relative Risk 0,67 in men (P<0.001)• Comparing the highest to lowest quintile of

intake

Magnesium and Type 2 Diabetes Risk

• Conclusion: ―”Our findings suggest asignificant inverse association betweenmagnesium intake and diabetes risk. Thisstudy supports the dietary recommendation toincrease comsumption of major food sourcesof magnesium, such as whole grains, nuts, andgreen leafy vegetables.”

Diabetes Care January 2004 vol. 27 no. 1 134-140doi: 10.2337/diacare.27.1.134

Magnesium Intake

Huerta MG, et al. Magnesium deficiency is associated with insulin resistance inobese children. Diabetes Care. 2005 May;28(5):1175-81

• Gallup poll 2004 commissioned by purdueProducts (makers a magnesium supplement)

• Low levels found in obese/overweightindividual.

• NHANES study 1999-2000 68% got less thanRDA, 19% consumed less than 50%. Low Mgincreases CRP and heart disease

― 80% not getting RDA just from diet― 35% getting RDA between diet and supplementsJuly 21, 2004 PRNewswire

JACN, Vol. 24, No. 3, 166-171 (2005)

Repletion of Magnesium

300 to 800 mg/day Range: elemental per dayBetter absorbed forms:Magnesium citrateMagnesium glycinateMagnesium taurateMagnesium malateMagnesium carbonate and oxide not effectivePercent Daily value at 300 mg/per day

Diabetes Care January 2004 vol. 27 no. 1 134-140doi: 10.2337/diacare.27.1.134

Magnesium Blood Levels

• Serum 1.7 - 2.2 mg/dL• RBC 4.2 - 6.8 mg/dL

• True measurement of magnesium tissuestatus is problematic as the serum level isnot reflective of tissue levels. RBC status mayimprove on this somewhat but it is still anissue

• Source Laboratory tests for the Assessmentof Nutrition Status Author: Howerde ESuberlich

Magnesium and Risk of Heart Disease

• 58,615 Japanese healthy men ages 40-79• Study 14.7 years• Increased magnesium intake in diet reduced

CVD mortality risk by 50%

Zhang, W, Iso, et al Associations of dietary magnesium intake with mortalityfrom cardiovascular disease : The JACC study. Atherosclerosis, vol. 221, Issue 2,April 2012 pg 587-595. doi:10.1016/j.atherosclerosis 2012.01.034

Magnesium and Stroke Risk

Meta Analysis• 7 studies pooled• For every 100mg increase intake magnesium

meant a 8-9% decreased total and ischemicstroke risk.

Larsson, N, orsini, Wolk, A. Dietary magnesium intake and the risk of stroke: ameta analysis of prospective studies; AmJClinNutr:doi:10.3495/acjn.111.031104

Eur J Clin Pharmacol. 1999 Apr;55(2):111-5.

Influence of beta-blockers on melatonin release.

Stoschitzky K1, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W.

Acta Psychiatr Scand. 2002 Dec;106(6):440-5.

Melatonin response to atenolol administration in depression: indication of beta-adrenoceptor dysfunction in a subtype of depression.

Paparrigopoulos T1.

J Am Coll Nutr. 1998 Feb;17(1):75-8.

Effects of captopril and enalapril on zinc metabolism in Hypertensive patients.

Golik A1, Zaidenstein R, Dishi V, Blatt A, Cohen N, Cotter G, Berman S, Weissgarten J.

Struktur ACE. Terdapat catalitic site pada lobus ekstraseluler,yang masing-masing mengikat zinc (Zn2+)

Digoxin Calcium; Mg, Phosphorus ↓ Urinary Excre on ↑

Mg deficiencies Cardiac disfungsi, Atrial Fibrillation

Propanolol – ↓ CoQ10 SuccinoxidaseCoQ10 – NADH – Oxidase

Metoprolol – HCTZ, Hydralazine, Clonidine inhibitCoQ10 – NADH – Oxidase

Methyldopa – ↓ weak succinoxidase inhibition

Kishi H. Et al. Res Con Chem Patho Pharmaco. 1975. 12 (3), 533-40

Anti Diabetic Drugs Sulfonylureas – deplete CoQ10

Biguanides: deplete CoQ10, B12, FA

Diabetes Care. 33: 156-161, 2010

Metformin : B12 ↓Homocystein Methylmalonic acid

Contrary to popular belief, stomatch acid secretions drop with advancing age.This graph shows average decline in stomatch acid secretion in humansBetween age 20 to age 80. (From “Why stomatch Acid is Good For You.”)

J Am Coll Nutr. 1991 Aug;10(4):372-5.

Inhibition of gastric acid secretion reduces zinc absorption in man.

Sturniolo GC1, Montino MC, Rossetto L, Martin A, D'Inca R, D'Odorico A, Naccarato R.

PPIs and WHI

• 47% more likely to have spine fracture• 26% more likely for forearm fracture• 25% more likely for any type fracture

Gray, S.L. Archives of Internal Medicine, May 10, 2010; vol 170:pp 765 -771.

130,000 women in the WHI on current PPI’s

Ann Intern Med. 1994 Feb 1;120(3):211-5.

Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12)

Marcuard SP1, Albernaz L, Khazanie PG.

CASE ICik Dep ♀ 59 th - Pensiunan Guru

- Diobati DPJP, dokter Specialist- Thiazide Diuretic- Diuril – Anti HTN- Fosamax – Osteoporosis- Beta Blocker - Tenormin untuk palpitasi

Cik Dep - Datang ke DPJP lain- Fatigue, anxietas, depresi, insomnia- Psychological examination- P.E/ no explanation, except stress/depresi- Terapi antidepressant- Terapi antianxietas pill- Terapi obat tidur

CASELaboratorium: Akibat obat terhadap micronutrient

- Potassium - Mg

ArrhytmiaHTNFatigueDepression

Diuretic Zn

Diagnosa Akhir : Cik DepDeficient 3 micronutrient : Mg++, K+, Zinc

Therapy 3 nutrient: Psychiatric symptoms ϴenergy & mood back to normal

KESIMPULANData-data/Informasi interaksi obat – nutrient banyak sekali penelitian-penelitian, terutama efek obat terhadap metabolism micronutrient. Apalagi masa sekarang banyak polypharmacy.

Pasien perlu discreen untuk defisiensi micronutrient sehubungan dengan diet, obat-obatan yang diresepkan, dan lifestyle.