DRUG

INTERACTIONS
& ADVERSE
DRUG
DRUG
INTERACTIO
NS
INSI
Penelitian di Kanada 1 Jan 1994—31 Des 2000
DEN
Case-control
Pasien > 65 th, ranap
 Sulfonylurea (glyburide)—sulfonamide  3,8%
hypoglycemia
 Digoxin—clarythromycin  2,6% digoxin toxicity
 ACE-inhibitor—potassium-sparing diuretic 8,2%
hyperkalemia
MEKANISME
Interaksi obat yg relevan secara klinis: efikasi atau toksisitas suatu obat—
INTERAKSI OBAT
substrat—yg diubah melalui penggunaan obat yg lain
Interaksi farmakodinamik
 Perubahan efek tanpa terjadi perubahan konsentrasi
 Erythromycin—amiodarone Toksisitas amiodarone (berupa perpanjangan QT)
 Acetaminophen—codeineAntinyeri yg efektif

Interaksi farmakokinetik
 Perubahan konsentrasi obat pada tempat aksi
 Perubahan ADME
 Variconazole—simvastatinrhabdomyolisis
PARADIGMA BARU INTERAKSI
Perubahan konsentrasi obat pada fase distribusi akibat ikatan plasma 
FARMAKOKINETIK
tidak lagi signifikan sbg penyebab
Bentuk tak terikat (unbound) didorong ke arah eliminasi (metabolisme
atau ekskresi)
E.g. warfarin (99% terikat,Vd = 9 L, fenitoin (90% terikat, Vd = 35 L,
tolbutamid (96% terikat, Vd = 10 L)
METABOLIS
ME OBAT

Neal, MJ, 2002, Medical Pharmacology at a Glance, 4th ed., Blackwell Science, p. 14
LANJUTAN
Kondisi yang mempengaruhi:
METABOLISME...
 Reaksi fase I: inflamasi dan infeksi
 Reaksi fase II: siroris

Bagaimana interaksi obat-obat terjadi pada fase metabolisme?

 Induksi atau inhibisi metabolisme substrat
INHIBISI
METABOLISME
Kapan dikatakan signifikan?
 Pada jalur metabolisme yg spesifik terhitung <= 30% dari total klirens
substrat
SUBSTRAT
Kompetitif: paling umum terjadi, inhibitor berikatan dengan
sisi katalitik
Non-kompetitif: jarang, sisi ikatan substrat dan inhibitor pada
enzim berbeda
Berapa lama onset inhibisi?
Reversibel atau
irreversibel?
 Chlarithromycin, erythromycin,
verapamil?
Nasib prodrug?
 Amiodarone—codeine
INDUKSI
METABOLISME
SUBSTRAT
Peningkatan sintesis enzim baru Onset induksi?
CYTOCHROME P450
Berhubungan dengan + 75-90% obat
ENZYME SYSTEM
CYP3A4 > CYP2D6 > CYP2C9 > CYP1A2 > CYP2E1 > CYP2C19
(Lihat
tabel-tabel pada referensi.)
DRUG
Pompa efflux or influx senyawa untuk melintasi
TRANSPORTING
membran Efflux transporter: P-glycoprotein
PROTEINS
Lokasi
 Sel epitel usus halus dan usus besar
 Membran kanalikuler hepatosit
 Tubulus proksimal ginjal
 Permukaan sel medula dan korteks kelenjar adrenal
 Duktul pankreas
 Sel epitel penyusun blood-brain barrier dan blood-testes barrier

Digoxin—erythromycin—Eubacterium lentum
LANJUTAN
DRUG... http://www.medscape.com/viewarticle/40623
6_2
LANJUTAN
Influx transporter:
DRUG...
 Organic anion transporting protein
(OATP)
 Organic cation transporter (OCT)

OATP
 Hati, ginjal, intestine, otak, plasenta
 Substrat: digoxin, rifampin, statin
 Statin—gemfibrozil

OCT
 Sekresi tubuler
 Probenecid—beta-lactam
BEBERAPA INTERAKSI
OBAT YANG FATAL
 Contoh Software
(Compendia)

A TRUE POSITIVE : CLINICALLY SIGNIFICANT DRUG

INTERACTION WAS IDENTIFIED.
A FALSE POSITIVE : INTERACTION WAS IDENTIFIED BUT
WAS NOT CLINICALLY IMPORTANT. A TRUE NEGATIVE :
CLINICALLY UNIMPORTANT DRUG INTERACTION WAS NOT
IDENTIFIED. A FALSE NEGATIVE : CLINICALLY
SIGNIFICANT INTERACTION WAS NOT IDENTIFIED.
LANJUTAN
Macam rekomendasi dari kompendia:
CONTOH…
 Hindari kombinasi
 Atur dosis obat substrat untuk menghindari toksisitas
 Pisahkan pendosisan untuk menghindari interaksi
 Jika tidak ada alternatif, monitor dan edukasi kpd pasien ttg tanda-tanda adverse
events
Referensi:
Schmidt, L.E., Dalhoff, K., 2002, Food-Drug Interactions [review article],
Drugs, 62(10): 1481-1502

DRUG-FOOD
INTERACTION
MEKA
NISME
Farmakokinetik, farmakodinamik
Karakteristik obat
Sifat fisika-kimia
Formulasi
Karakteristik makanan
Porsi dan komposisi makanan
Bioavalabilitas obat lipofil dgn makanan berlemak?
 Peningkatan kelarutan (albendazole, isotretinoin) atau
 Stimulasi sekresi empedu (griseovulfin, halofantrine)
Bioavailabilitas beberapa obat berkurang (digoxin, lovastatin) dgn makanan berserat
 Mengapa?
Definisi “tanpa adanya makanan”?
RANGKUMAN OBAT-OBAT YANG
DIREKOMENDASIKAN UNTUK DIGUNAKAN
BERSAMA MAKANAN
Albendazole
Griseofulvin
Isotretinoin
Itraconazole
(kapsul) Lovastatin
Saquinavir
Tacrolimus
RANGKUMAN OBAT-OBAT YANG
DIREKOMENDASIKAN UNTUK DIGUNAKAN TANPA
MAKANAN
Ampicillin
Ciprofloxacin
Didanosine
Erithromycin
Halofantrine
Indinavir
Itraconazole
(sol) MAO
Inhibitor
Spironolactone
Tetracycline
Referensi:
Fuhr, U., 1998, Drug Interactions with Grapefruit Juice Extent,
Probable Mechanism and Clinical Relevance [drug experience],
Drug Safety 18(4):251-272, Adis International Limited

DRUG
INTERACTI
ON WITH
GRAPEFRUI
GJ DAN
FELODIPINE Studi interaksi felodipine-alcohol oleh
Bailey et al.  dikonfirmasi oleh 9
studi lainnya
AUC dan Cmax ↑
Half-life tidak berubah
Dosis GJ: 200-500
mL
KANDU
NGAN Citrus paradisi
Naringenin (flavonoid), inhibitor CYP3A4
Turunan coumarin dan psoralen
(furocoumarin)
 Psoraleninhibitor poten thd CYP3A4 pada hati
tikus dan manusia
REKOME
NDASI
 Hindari konsumsi secara bersamaan (obat yg terbukti maupun diduga berinteraksi
dengan GJ)
 Verapamil
 Terfenadine
 Cyclosporin
 Ethinylestradiol
 Prednisone
 Midazolam
 Quinidine
 Saquinavir

Pelabelan produk obat (GJ coret)

Referensi:
Izzo, A.A., 2004, Herb-Drug interactions: an overview of the clinical evidence
[review article], Fundamental & Clinical Pharmacology, 19(2004): 1-16

DRUG-HERBS
INTERACTION
Sebuah survei
 2 dari 3 perempuan menggunakan herbal untuk gejala menopause
 45% ortu memberikan herbal treatment kpd anaknya
 45% perempuan hamil mencoba pengobatan herbal

Produk herbal, natural, dipromosikan tdk berbahaya; tapi tetap tidak bebas dari
adverse effects
Obat-obat herbal biasa berisi lebih dari 100 bahan aktif (! Lihat konteks tulisan)
MEKA
NISME
Farmakokinetik
 Penelitian >>
 CYP hepatik/intestinal
 Herbal, e.g. St. John’s Wort, echinaceae, garlic
 Isolat herbal, e.g. flavonoid, coumarin, caffeine
 P-glycoprotein,e.g. curcumin, ginsenoside, piperine, catechin

Farmakodinamik
 Penelitian <<
 Additive (sinergistic), herbal mempotensiasi aksi obat sintetis, e.g. antikoagulan
warfarin dengan herbal antiplatelet
 Antagonistic, herbal mereduksi efikasi obat sintetis, e.g. kava dan levodopa
ADVERSE DRUG
REACTIONS
 Ref: Edwards, IR, Aronson, JK,

DEFINITION
2000, Adverse drug reactions:
definitions, diagnosis, and
management, The Lancet, 356,

AND SCOPE p. 1255-1259

WHO
1972
A response to a drug that is noxious and unintended and occurs at doses normally
used in man for the prophylaxis, diagnosis or therapy of disease, or for
modification of physiological function.

Problems:
 Including minor adverse reactions, e.g.?
 Excluding error as a source of adverse effects
EDWARDS &
ARONSON, 2000
Proposed definition of adverse drug reaction:
An appreciably harmful or unpleasant reaction, resulting from an intervention
related to the use of a medicinal product, which predicts hazard from future
administration and warrants prevention or specific treatment, or alteration of the
dosage regimen, or withdrawal of the product.
WHO’S ADVERSE DRUG
REACTION TERMINOLOGY
(WHO-ART), 1992
An adverse drug reaction (ADR) is ‘a response to a medicine which is noxious
and unintended, and which occurs at doses normally used in man’.
It concerns:
 the response of a patient, in which individual factors may play an important role,
 the phenomenon is noxious (an unexpected therapeutic response, for example, may be a side effect
but not an adverse reaction).

Currently accepted international terminology of ADR

Main goal: improving pharmacovigilance communication, integrated with
other WHO’s project: International Classification of Diseases (ICD, 10th
version)
 And, there still have a problems: combining the terminology with bibliographic databases

www.who-umc.org (Uppsala Monitoring Centre)

SO, THE
DIFFERENCES
Side Effect Toxic Effect
ARE ...
Occured in normal dose Occured in overdose
Not always dose-dependent Always dose-dependent
Not via therapeutic effect Via therapeutic effect
Might be beneficial Always harmful
E.g.
 Anaphylaxis of penicillins
E.g.
 a headache due to a calcium antagonist is a
 Anticholinergic activity of
toxic effect (vasodilatation)
tricyclic antidepressants
 Beta-blocker activity for
hypertension and angina
ADR, SIDE EFFECT,
AND TOXIC EFECT
Side
Effec Adverse Adverse
t Effect Drug
Advers  Reactio
n
from
e point of 
from
Toxi Effect view of
the drug point
of
c view of
Effec patient
t
 Ref: Aronson JK, Ferner RE,
2003, Joining the DoTS: new
CLASSIFICATIO approach to classifying adverse
drug reactions, BMJ, 327, p.
http://www.bmj.com/content/327
1222-1225

N SYSTEM
/7425/1222.full
TY
PES
Old, but commonly used: mnemonic system (ABCDEF)
Newly proposed: DoTS, in relation to dose, time, and
susceptibility
A (AUGMENTED)
BCDEF - MNEMONIC
Dose dependent
Predictable from the known pharmacology of the drug
Common and low mortality
Case:
 Digoxin toxicity
 Serotonine syndrome with SSRIs
 Anticholinergic effects of tricyclic antidepressants
AB
(BIZARRE)
Non dose dependent
CDEF
Unpredictable from the known pharmacology of the drug
Uncommon and high mortality
Case:
 Penicillin hypersensitivity
 Acute porphyria
 Malignant hyperthermia
ABC
(CHRONIC)
Dose-related and time-related
DEF
Uncommon
Related to the cummulative
dose Case:
 Hypothalamic-pituitary-adrenal axis
supression by corticosteroids
ABCD
(DELAYED)
Time-related and usually dose-related
EF
Uncommon
Occurs or become apparent after some time the use of the drug
Case:
 Vaginal adenocarcinoma with diethylstilbestrol
 Carcinogenesis
 Tardive dyskinesia
ABCDE (END
OF USE) F
Withdrawal

Uncommon
Occurs soon after withdrawal of the drug
Case:
 Opiate withdrawal syndrome
 Myocardial ischaemia (beta-blocker withdrawal)
ABCDEF
(FAILURE)
Unexpected failure of therapy
Common
Dose-related
Often caused by drug interactions
Case:
 Inadequate dosage of an oral
contraceptive when used with specific
enzyme inducers
THE DOTS
CLASSIFICATIO
N
DO (DOSE
RELATEDNESS)
Supratherapeutic doses  toxic dose
TS
Collateral effects, at standard/ normal therapeutic dose  commonly named side
effect
Hypersusceptibility reactions
DOT (TIME
RELATEDNESS)
Time independent reactions
STime dependent reactions
 Rapid reactions, e.g. the red
man syndrome with
vancomycin
 First dose reactions, e.g.
Hypotension after the first dose
of an ACE-inhibitor
 Type I hypersensitivity reactions
 Early reactions, e.g. Nitrate
induced headache
 Intermediate reactions, e.g.
Type II-IV hypersensitivity
reactions
 Late reactions, e.g. Adverse effects of corticosteroids, tardive dyskinesia with dopamine receptor
antagonists
 Delayed reactions, e.g. Teratogenesis due to thalidomide
DOTS
(SUSCEPTIBILITY
Genetic, e.g.
SOURCES)
 Porphyria
 Malignant hyperthermia
 CYP isoenzyme
polymorphism

Age, e.g.
 Neonates and chloramphenicol
 Elderly people with hypnotics
DOTS
(SUSCEPTIBILITY
Sex, e.g.
SOURCES)
 Alcohol intoxication
 Mefloquine and neuropsychiatric effect
 ACE-inhibitor and cough
 Lupus-like syndrome

Physiology altered, e.g.

 Phenytoin in pregnancy
DOTS
(SUSCEPTIBILITY
Exogenous factors, e.g.
SOURCES)
 Drug interactions
 Interactions of GJ with drugs metabolized by
CYP3A4

Disease, e.g.
 Renal insufficiency with lithium
 Hepatic chirrosis with morphine
 Ref: Agbabiaka, T.B., Savović,

CAUSALITY J. & Ernst, E., 2008. Methods

for Causality Assessment of
Adverse Drug Reactions: A
ASSESSMENT OF Systematic Review. Drug
Safety, 31(1),

SUSPECT p.21-37.

ED ADR
CAUSAL RELATIONSHIP
BETWEEN DRUG AND
ADVERSE EFFECTS

DRUG METHOD Advers

(S)
OF
ASSESSME e
NT
Effects
METHODS FOR
CAUSALITY
Banyak metode Pertama kali dimulai oleh Hill (1965)
ASSESSMENT
Setiap metode memiliki kelebihan dan
 Strength of the association
 Specificity
kekurangan  Temporality of the association
HINGGA SAAT INI TIDAK ADA  The biological gradient (dose-response curve)
satu pun  Plausibility
yang diterima sebagai GOLD-  Coherence
STANDARD  Experiment
 Analogy
Agbabiaka et al., 2008
 Drug including herbal medicine,
vitamin, and supplement
 Validity and reproducibility: EJ or GI
Expert Judgement or
<< Algorithms << Probabilistic or
Bayesian Approaches
Global Introspection
(4)

Method
s

Probabilistic or
Bayesian
Approaches (4)
Algorithm
s (26)
EXPERT JUDGEMENTS OR
GLOBAL INTROSPECTION
Identifikasi ADR sering tergantung pada dokter
 Klinisi yang sedang menangani pasien atau
 Farmakolog klinis

Individual assessment based on previous knowledge and experience in the field using
no standardidized tool to arrive at conclusions regarding causality
E.g.:
 Wilholm (1984)
 WHO UMC (2007)
 Miremont et al. (1994)
 Arimone et al. (2005)
WHO
UMC
WHO
UMC
ALGORI
THMS
Algorithm is a problem-specific E.g.:
flow chart with step-by-step  Irey (1976)
instruction on how to arrive at an  Karch and Lasagna (1977)
answer.  Kramer et al. (1979)
 Naranjo et al. (1981)
Sets of specific questions with
 RUCAM (Danan and Benichou,
associated scores for calculating the
1993)
likelihood of a cause-effect relationship.
 Horn et al. (2007)
Structured and standardized
High degree of consistency and
reproducibility
ALGORI
THMS
Naranjo et al. (1981)
 Very simple
 Only one drug, not for ADR from drug interactions netween 2
drugs
 Not appropriate for DILI (Drug-Induced Liver Injury)
 Assessment from 2 physicians and 4 pharmacists
ALGORI
THMS
NARAN
JO’S
ALGORI
THMS
NARAN
JO’S
PROBABILISTIC OR
BAYESIAN APPROACHES
Use specific findings in a case to transform the prior estimate of probability into a
posterior estimate of probability of drug causation.
 The prior probability is calculated from epidemiological information
 The posterior probability combines background information (the epidemiological information) with
the evidence in the individual case to come up with an estimate of causation.

E.g., spreadsheet:
 Marshford (1984)  The Australian method
 Lane et al. (1987)  including Kramer
PROBABILISTIC OR
BAYESIAN APPROACHES
Computer programs:
 The Bayesian Adverse Reaction Diagnostic Instrument
(BARDI)
 MacBARDI-Q&A  including Naranjo
EXAMPLE BY CASES
ARONSON, J.K., DUKES, M.N.G. & MEYLER, L., 2006. MEYLER’S SIDE EFFECTS OF

ACE- Non-productive Irritant

DRUGS: THE INTERNATIONAL ENCYCLOPEDIA OF ADVERSE DRUG REACTIONS
Inhibitors Cough Prolonged QT
Antihistamine
AND interval
INTERACTIONS, ELSEVIER.
 Biguanides Lactic acidosis

NON-PRODUCTIVE IRRITANT COUGH
DUE TO ACE-INHIBITOR

DoTS classification
Dose-relation: collateral effect
Time-course: time-
independent
Susceptibility factors: genetic (polymorphisms of the bradykinin B2 receptor gene
and the ACE gene); sex (men); exogenous factors (non-smokers).

The dose-relatedness of this adverse effect is not clear.

NON-PRODUCTIVE IRRITANT COUGH
DUE TO ACE-INHIBITOR
NON-PRODUCTIVE IRRITANT COUGH
DUE TO ACE-INHIBITOR
NON-PRODUCTIVE IRRITANT COUGH
DUE TO ACE-INHIBITOR
FREQUENCY
In different studies there has been large variability in the
 absolute incidence of cough (0.7–48%),
 the discontinuation rate (1–10%), and
 the relative incidences with different ACE inhibitors.
NON-PRODUCTIVE IRRITANT COUGH
DUE TO ACE-INHIBITOR
MECHANISM
It may be more complicated than just an increase in concentrations of bradykinin and
substance P, increased microvasculature leakage, and stimulation of vagal C fibers.
Common variant genetics of ACE, chymase, and the bradykinin B2 receptor do not
explain the occurrence of ACE inhibitor-related cough.
In general, bronchial hyper-reactivity has been causally implicated and may also be
associated with exaggerated dermal responses to histamine.
NON-PRODUCTIVE IRRITANT COUGH
DUE TO ACE-INHIBITOR
SUSCEPTIBILITY FACTORS
Cough is more common in
 Non-smokers,
 Women,

Chinese patients experience more cough from ACE inhibitors than

Caucasians. It has been speculated that the risk of cough is genetically
predetermined.
NON-PRODUCTIVE IRRITANT COUGH
DUE TO ACE-INHIBITOR
MANAGEMENT
ACE inhibitor-associated cough seems to be a class effect: switching to another
ACE inhibitor rarely solves the problem, although there are occasional anecdotal
reports.
However, most patients who develop a cough related to an ACE inhibitor are
able and willing to continue therapy.
In a small randomized study inhaled sodium cromoglicate relieved the
symptom.
In those in whom the symptom is intolerable, a switch to an angiotensin
receptor antagonist is justified.
ANTIHISTAMINE EFFECT ON
CARDIOVASCULAR
Prolonged QT interval and ventricular
dysrhythmias DoTS classification
 Dose-relation: toxic effect
 Time-course: time-independent
 Susceptibility factors: genetic (long QT syndrome); altered physiology (hypokalemia); drug
interactions (metabolism inhibitors; drugs that prolong the QT interval); diseases (liver disease;
cardiac disease with prolongation of QT interval)
ANTIHISTAMINE EFFECT ON
CARDIOVASCULAR
ANTIHISTAMINE EFFECT ON
CARDIOVASCULAR
First reported with astemizole and later with terfenadine.
 A dose-dependent effect on cardiac repolarization
 Cause prolongation of the QT interval, which can lead to ventricular dysrhythmias (such as torsade
de pointes), syncope, and cardiac arrest.

Reported cases relate preponderantly to overdosage, especially in children.

ANTIHISTAMINE EFFECT ON
CARDIOVASCULAR
PHARMACOKINETICS
Antihistamines are
 rapidly and completely absorbed after oral administration;
 peak plasma concentrations are reached after 1–4 hours and are highly
variable, owing to differences in tissue distribution and metabolism.

Many of the second-generation antihistamines (for example

astemizole, ebastine, loratadine, and terfenadine) undergo
extensive first-pass metabolism to pharmacologically
active metabolites  primarily supported by CYP3A4.
ANTIHISTAMINE EFFECT ON
CARDIOVASCULAR
PHARMACOKINETICS
Under normal circumstances this extensive metabolism leads
to low or undetectable plasma concentrations of the parent
drug.
However, sometimes metabolism of the parent compound can
be compromised.
ANTIHISTAMINE EFFECT ON
CARDIOVASCULAR
MECHANISM
Accumulation of unmetabolized astemizole or terfenadine
can result in blockade of cardiac potassium channels in the
ventricular myocytes that regulate the duration of the action
potential; consequent prolongation of the QT interval can result
in potentially life-threatening ventricular tachycardia.
ANTIHISTAMINE EFFECT ON
SUSCEPTIBILITY
CARDIOVASCULAR FACTORS
Dysrhythmias can also occur with therapeutic doses of these
and other antihistamines, if certain other susceptibility factors
are present:
 impaired hepatic metabolism due to liver disease;
 simultaneous treatment with drugs that are inhibitors of the cytochrome
P450 enzyme CYP3A4 (for example macrolide antibiotics, antifungal
azoles, or grapefruit juice), leading to increased plasma concentrations
thereby raising the risk of cardiotoxic effects;
ANTIHISTAMINE EFFECT ON
SUSCEPTIBILITY
CARDIOVASCULAR FACTORS
 pre-existing QT prolongation caused by congenital long QT syndrome, other
heart disease, or treatment with antidysrhythmic drugs, such as class I
antidysrhythmic drugs, amiodarone, or sotalol;
 electrolyte imbalance; in particular, hypokalemia predisposes to
Dysrhythmias.
LACTIC ACIDOSIS DUE
TO BIGUANIDES
DoTS classification
Adverse effect: Lactic acidosis due to biguanides
 Dose-relation: toxic effect
 Time-course: time-independent
 Susceptibility factors: genetic (slow phenformin metabolizers); age; disease (impaired liver, kidney,
or cardiac function, alcoholism)
LACTIC ACIDOSIS DUE
TO BIGUANIDES
LACTIC ACIDOSIS DUE
TO BIGUANIDES
Biguanides can cause lactic acidosis, which is fatal in 50% of cases.
A 65-year-old man with a creatinine clearance of 67 ml/minute taking 13,
metformin 850mg bd developed lactic acidosis (lactate 25 mmol/l, pH 7,
bicarbonate 5 mmol/l) . Despite the relatively small dosage of metformin, he had
unexplained very high metformin concentrations (61 mg/ml).
 A possible explanation for the high metformin concentration in this case was that an unknown
substance related to intestinal inclusion inhibited its tubular excretion.
LACTIC ACIDOSIS DUE
TO BIGUANIDES
Other cases involving metformin have included the following:
 a 62-year-old woman: pH 6.60, blood lactate 45 mmol/l, creatinine 133 mmol/l (33);
 a 72-year-old woman: pH 6.84, creatinine 125 mmol/l (34);
 a 75-year-old woman: pH 6.73, lactate 18 mmol/l (34);
 a patient with creatinine 91 mmol/l, creatinine clearance 52 ml/minute, metformin concentration 61
mg/ml (target under 5 mg/ml) (35);
 a 52-year-old woman, a chronic alcohol user: pH 6.74, lactate over 30 mmol/l, creatinine 710 mmol/l
(36);
 an 83-year-old woman with mild renal insufficiency (37).

All survived, but all needed hemodialysis.

LACTIC ACIDOSIS DUE
TO BIGUANIDES
INCIDENCE
In patients taking metformin, lactic acidosis is rare (3 per 100 000 patient-years)
Most often seen when contraindications to metformin (impaired kidney or liver
function, alcoholism, circulatory problems, old age) are neglected or not detected.
LACTIC ACIDOSIS DUE
TO BIGUANIDES
MECHANISM
Biguanides in high doses inhibit the oxidation of carbohydrate substrates by affecting
mitochondrial function.
Anoxidative carbohydrate metabolism stimulates the production of lactate.
High lactate production leads to lactic acidosis (type B) with a low pH
(<6.95).

Hyperlactatemia was common in patients taking buformin, even without alcoholism

or impaired liver, kidney, or cardiac function.
LACTIC ACIDOSIS DUE
TO BIGUANIDES
SUSCEPTIBILITY
The main susceptibility factor for lactic acidosis due to metformin is
FACTOR
renal insufficiency
Drugs that can precipitate lactic acidosis in patients taking metformin include: ACE
inhibitors, thiazide diuretics, NSAIDs, and drugs such as furosemide, nifedipine,
cimetidine, amiloride, triamterene, trimethoprim, and digoxin, which are all
secreted in the renal tubules, compete with metformin, and can contribute to
increased plasma metformin concentrations.
LACTIC ACIDOSIS DUE
TO BIGUANIDES
PRESENTATIONS
The early symptoms of lactic acidosis are nausea, vomiting, and diarrhea; since these
are common adverse effects of biguanides, a careful watch should be kept for their
sudden onset or aggravation, which might point to lactic acidosis.
LACTIC ACIDOSIS DUE
TO BIGUANIDES
MANAGEMENT
The best therapy of metformin-induced lactic acidosis is immediate
hemodialysis, but metformin in the tissues continues to produce lactate while the
drug is being removed during dialysis.
Sodium bicarbonate is not very effective and can paradoxically lower the pH and
cause hypernatremia and fluid overload.
Tracheal intubation and mechanical ventilation may be necessary.
LACTIC ACIDOSIS DUE
TO BIGUANIDES
MANAGEMENT
Theophylline and dichloroacetate have also been used.
 Theophylline stimulates oxygen exchange in the lungs.
 Dichloroacetate activates pyruvate dehydrogenase, inhibiting lactate formation, but it is neurotoxic, can
cause cataract, and is mutagenic.
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