curiculum vitae

CURICULUM VITAE
CURICULUM VITAE
A.Personal Data
Nama Lengkat/Gelar
Tempat/Tanggal Lahir
Alamat
Phone
Email
:Prof. dr. Hardi Darmawan, MPH&TM, FRSTM, DAFK
: Palembang, 24 November
:Jl. Ismail Marzuki No. 220/4235, Kel. Sekip Jaya, Palembang
:0711-353 374
:[email protected]
B.Working Experience
RS RK Charitas
1.Ka. Lab. Klinik
2.Ka. Bid. Diagnostik
3.Direktur Penunjang Medik
4.Direktur Kerja Sama Antar Instansi dan Hubungan Luar Negeri
5.Direktur Keuangan, Logistik & SDM
6.Direktur Utama
C.Education
1.Fakultas Kedokteran Universitas Sriwijaya – Dokter Umum
2.Tulane University, USA – Master of Public Health and Tropical Medicine
3.London, United Kingdom – Fellow of The Royal Society of Tropical Medicine and Hygiene
4.Kolegium Ikatan Ahli Ilmu Faal Bandung / FK Unpad – Ilmu Faal / Fisiologi
5.Ikatan Dokter Indonesia – Ilmu Faal / Fisiologi
Defisiensi Mikronutrient Akibat Pemberian Obat-obatan
Jangka Panjang
Topik yang jarang sekali dibicarakan/dipresentasikan (A Story Rarely Told)
Disampaikan Oleh: Prof. dr. Hardi Darmawan, MPH&TM, FRSTM, AIFI.,M
Rumah Sakit RK. Charitas Palembang
Fakultas Kedokteran UNSRI Palembang
Disampaikan dalam SEMINAR NASIONAL PERUMAHSAKITAN & RAPAT KERJA NASIONAL PERSI
26 Juli 2017
Objectives
1. To review
micronutrient-drug
interactions.
2. To increase awareness
of micronutrient-drug
interactions for patient
safety and wellness.
“Nungcik” 35 Thn
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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
Prevalensi Mikronutrient Defisiensi
Etiology
Faktor- faktor Resiko
Physiology of Drugs
Physiology of Nutrient
Pathophysiology of Drug Induced
Micronutrient Depletion
Food-Nutrient Interaction
Drug-Nutrient Interaction
Case Studies
Kesimpulan
Latar Belakang
• Vitamin dan Trace Elements adalah penting
sekali untuk fungsi tubuh manusia
• Required Allowance – Food Intake
• Deficiency Nutrients – Structural, Functional
Dysfunction
Reversible
Supplementation
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
Physiology of Drugs
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
Pathophysiology of Drug/Food
Induced
Efek Makanan/Obat terhadap Mikronutrient
•
•
•
•
•
Tipe pengobatan
Bentuk obat: pil/tablet, cairan/sirup
Dosis
Tempat absorpsi : mulut, lambung, usus
Rute pemberian: oral, intravena, IV/Im, s.c
3 Main Types of Drug Interactions
1.Drugs with food
and beverages
2.Drugs with dietary
supplements
3. Drugs with other
drugs
Nutrient – Drug Interactions
Medications can affect nutrients by:
1.
2.
3.
4.
5.
Decreasing food intake
Decreasing nutrient absorption
Slowing down nutrient production
Interfering with nutrient metabolism
Increasing nutrient excretion
Nutrient-Drugs Interactions
Nutriet - Drugs Interactions is a consequence of physical,
chemical or pathophysiologic relationship between a
drug 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 the
therapeutic drug response and/or compromise
nutritional status.
Nutrient-Drugs Interactions
The interaction can therefore alter the therapeutic
response.
• The interaction can result in decreased bioavailability
of drug causing treatment failure or increased
bioavailability causing toxicity and adverse effects.
• The patient’s
nutritional status and dietary
components with pharmacological activity can affect
drug metabolism thereby altering action and function.
Nutrient-Drugs Interactions
Drug can play a significant role in developing nutrient
deficiencies.
• Drug-induced micronutrient depletion may be
responsible for the unexplained symptoms that affect
medication compliance (zinc and ACE inhibitors and
ARAII).
Many micronutrients are potentially vulnerable to the
effects of prescribed medicines when consumption is
regular and sustained.
Nutrient-Drugs Interactions
Vitamin and trace elements are essential to the
body
Micronutrients are required for intermediary
metabolism in varying amounts-usually < 1 gram/day to
as low as a few micrograms/day
Nutrient-Drugs Interactions
Fruits, vegetables, herbs and teas contain a large variety
of micronutrients and phytochemicals that have been
associated with health benerfits.
These however consist of complex phytochemicals that
can inhibit or induce the activity of cytochrome (CYP)
P450 family of enzymes
Food-Nutrient Interaction
Common Interaction
Alkohol
> 3x minum
alkohol/hari
Alkohol
> 3x minum
alkohol/hari
─ Acetaminophen
Serious
Liver
Damage
+ NSAID
Perdarahan
Lambung
Food-Nutrient Interaction
 Buah-buahan, sayur-sayuran, herbal dan teh mengandung
beberapa micronutrients – phytochemical yang baik untuk
kesehatan.
inhibit
 Phytochemicals complex
Aktivitas CYP
induce
(Cytochrome) P450
enzyme
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 taken
simultaneously with the medication in order to produce
the interaction.
The bioavailability of drugs can be doubled by
grapefruit juice even several hours after
ingestion
ACTION : Grapefruit and grapefruit juice shall not be
included as patient menu selections
Chocolate
• The caffeine in chocolate can cause the
effects of stimulant medications (including
methyl phenidate) to be intensified.
• Opposite effects with sedatives – can cause
their intended effects to be decreased.
• One ounce of dark chocolate can contain up
to 35gm of caffeine, enough to potentially
cause a problem.
Chocolate
• Chocolate also contains tyramine, a chemical
that controls blood pressure.
• If taking MAOI’s to treat depression, tyramine
can cause a dangerous increase in blood
pressure, potentially leading to a stroke.
Chocolate
 Caffeine di dalam chocolate  stimulant medication
Methylphenidate
 1 ons dark chocolate  35 gram caffeine  problem prone
 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
Dying for a cup of tea.
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
Abstract
We report the case of a 70-year-old woman who developed lifethreatening 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.
Ginseng
Interferensi the bleeding effect of coumadin
Bleeding effects of heparin, aspirin, NSAID
Ginko Biloba
An convulsants ↓  control kejang ↓
Selected Drugs that Interact with Grapefruit
& Other Fruits Containing Furanocoumarins
Antilipemic
Agents
Atorvastatin,
Lovastatin
Simvastatin
Cardiovascular agents
Felodipine
Nifedipine
Quinidine
Verapamil
Eplerenone
Ticagrelor
Amiodarone
Apixaban
Clopidogrel
Dronedarone
Rivaroxaban
Quinidine
Alternatives with the same therapeutic indication
that have no or minor interaction
Pravastatin,
Rosuvastatin
Fluvastatin
Amlodipine
Acetylsalicyclic
Warfarin
Sotalol
Spironolactone
Cholesterol Lowering Drugs
HmG-CoA Reductan
Inhibitors 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-CoA
Reductase
Inhibitors
(Statins)
Ubiquinone
STATINS
Coenzyme Q10
STATIN  TESTOSTERONE ↓ (Giovanni Corona, MD)
Early death of Heart disease
Chris Malkin, 2010; Ronald. Heart, 2010
Sleep
E. Leproult, 2011. JAMA
• Obesity
• Metabolic Syndrome
• Insulin Resistance
• Diabetes
• CVD
CoQ10↓
Groosman J. Diri Endo. 2006
•  Obesity DM Type II
• Myopathies
• Muscle Fibers
Free Rad Res. 2002. 36(4). 445-453
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, 1990
Force & Nabate. Ann Rhesni. 1992 (26 – 1283 – 81)
Anti Hypertensive Drugs
 Hydralazine : B6, CoQ10
 Loop : Ca, Mg, K, Zn, B1, B6, C
 Thiazide : Mg, K, Zn, CoQ10
 Potassium Sparing: Ca, Zn, FA
 Beta Blocker : CoQ10, Melatonin
 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 old
problem.” 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 and
Diabetes 15 year follow up 608 cases MetS.
-Studies suggest magnesium intake may be
inversely related to risk of hypertension and type
2 diabetes mellitus:
-Higher intake of magnesium may decrease
blood triglycerides and increase high-density
lipoprotein (HDL) cholesterol levels.
Circulation: Epidemiology: Magnesium Intake and Incidence of Metabolic
Syndrome Among Young Adults 2006; 113: 1675-1682 Published online before
print March 27, 2006, doi:10.1161/CIRCULATIONAHA.105.588327
Magnesium cont’d
• Magnesium intake inversely related to
individual component of the metabolic
syndrome and fasting insulin levels.
• Conclusion― “Our findings suggest that
young adults with higher magnesium intake
have lower risk of development of metabolic
syndrome”.
Magnesium
Magnesium supplementation 500 mg elemental
form for 4 wk in overweight individuals: distinct
changes in gene expression
•
•
•
•
 C-peptide .4ng/ml
 Insulin -2.2uU/ml
24 gene up regulation and 36 down regulation
All related to metabolic and inflammatory pathways
Trial registered at clinicaltrials.gov as NCT00737815
Magnesium Supplementation, metabolic and inflammatory markers, and global
genomic and proteomic profiling: a randomized double-blind, controlled,
crossover trial in overweight individuals Chacko, Sara, Sul, James, Song, Yiqing
et al; Am J Clin Nutr February 2011 vol 93 no2 463-473
 Magnesium Status due to decrease
Diatary intake or Altered metabolism
Clotting
• Pre-thrombotic state
Insulin resistance
• Impaired glucose tolerance
Hypertension
• Sm. Muscle contractility
• Endothelial dysfunction
• Aleration of response
angiotensin II, endothelin
Dyslipidemia
• HDL LDL TG
• HMGCoA
• LDL
Inflammation
• IL-1 IL-6 TNF-
• Adiponectin
Oxidative Stress
• Lipid oxidation
• Vascular Remodeling
• Endothelial dysfunction
Magnesium Research. Volume 20, Number 2, 107-29, June 2007, Review article
DOI : 10.1684.mrh.2007.0096
Magnesium Intake and Risk of Type 2
Diabetes in Men and Women
• 85,600 women and 42,872 men no Hx
diabetes 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 a
significant inverse association between
magnesium intake and diabetes risk. This
study supports the dietary recommendation to
increase comsumption of major food sources
of magnesium, such as whole grains, nuts, and
green leafy vegetables.”
Diabetes Care January 2004 vol. 27 no. 1 134-140
doi: 10.2337/diacare.27.1.134
Magnesium Intake
• Gallup poll 2004 commissioned by purdue
Products (makers a magnesium supplement)
― 80% not getting RDA just from diet
― 35% getting RDA between diet and supplements
July 21, 2004 PRNewswire
• Low levels
individual.
found
in
obese/overweight
Huerta MG, et al. Magnesium deficiency is associated with insulin resistance in
obese children. Diabetes Care. 2005 May;28(5):1175-81
• NHANES study 1999-2000 68% got less than
RDA, 19% consumed less than 50%. Low Mg
increases CRP and heart disease
JACN, Vol. 24, No. 3, 166-171 (2005)
Repletion of Magnesium
300 to 800 mg/day Range: elemental per day
Better absorbed forms:
Magnesium citrate
Magnesium glycinate
Magnesium taurate
Magnesium malate
Magnesium carbonate and oxide not effective
Percent Daily value at 300 mg/per day
Diabetes Care January 2004 vol. 27 no. 1 134-140
doi: 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 tissue
status is problematic as the serum level is
not reflective of tissue levels. RBC status may
improve on this somewhat but it is still an
issue
Source Laboratory tests for the Assessment
of Nutrition Status Author: Howerde E
Suberlich
•
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 mortality
from 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 ischemic
stroke risk.
Larsson, N, orsini, Wolk, A. Dietary magnesium intake and the risk of stroke: a
meta 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 Succinoxidase
CoQ10 – NADH – Oxidase
 Metoprolol –
HCTZ, Hydralazine, Clonidine inhibit
CoQ10 – 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
 Metformin : B12 ↓
Homocystein 
Methylmalonic acid 
Diabetes Care. 33: 156-161, 2010
Contrary to popular belief, stomatch acid secretions drop with advancing age.
This graph shows average decline in stomatch acid secretion in humans
Between 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
130,000 women in the WHI on current PPI’s
• 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.
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 I
Cik 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
CASE
Laboratorium:
Akibat obat terhadap micronutrient
- Potassium 
Arrhytmia
- Mg 
HTN
Fatigue
Depression
Diuretic  Zn 
Diagnosa Akhir : Cik Dep
Deficient 3 micronutrient : Mg++, K+, Zinc
Therapy 3 nutrient: Psychiatric symptoms ϴ
energy & mood back to normal
KESIMPULAN
Data-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.