2 December 1951

Bukit Tinggi
MD, FK USU, 1978
PhD in Clinical Pharmacology
FUSA-Flinders Medical Centre
Australia, 1988
SpFK, Clinical Pharmacologist
PB-IDI & FK UI, 1995
Professor
Head of Department
Pharmacology & Therapeutic
School of Medicine, USU
Email: aznanlelo@yahoo.com

Jln. Tridharma 22
Kampus USU, Medan

Aznan Lelo
Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera
Utara
7 Oktober 2011,
KONKER IPS, Jakarta

Rajin-rajin belajar ya nak,

supaya pintar dan jadi

Kata orang
Mereka semua ter-lahir pintar dan
baik,
Namun selanjutnya jadi bodoh dan
jahat.
Lalu dimana kesempatan itu?

Bahaya = Dangerous
Risk
factors

Doctor
shoppin
g

patien
t

etc

Docto
r
RDA
Surgery
etc

therap
y

OTC

drug

Herbal
med.
etc

IATROGENIK
(iatro = dokter)

Dangerous
Doctor ?

Sakit kepala
Sakit gigi

Novalgin

Bisulan

Ponstan

Nyeri haid

Voltaren

Rematik
Gout

Feminax
Irgapan

Celebrex

Tapi, saya mudah sesak

dan sering kencing malam

Nyeri bahu
Nyeri pinggang
Nyeri lutut
Nyeri tumit

yang penting hilangkan NYERI-nya

urusan JANTUNG, belakangan

s
ain

etc,
etc,etc
etc
Sakit ?
Nyeri
bisul

Pegal
Linu

Asam
mefenamat
Nyeri
dada

Nyeri
haid
Sakit
in-partu
Sakit
gigi

Sakit kepala

Campuran yang
mematikan

Gatal
Sesak

Tramadol
CTM

Menceret
Tak bisa
tidur

Salbutamol

Imodium
Diazepam

Sakit kepala

Sudah keluargaku
mati
Uangku pula yang
habis

Sakit gigi

Novalgin
Rp

Bisulan

Ponstan
Rp

Rematik

Voltaren
Rp

Gout
Irgapan
Rp

Confortid
Rp

Dangerous person
Wishing to eliminate a
president of another
country
Bombing all areas of
the country
Killing the people in
that country
Spending 20 M US$
But then offering only
200,000 US$ to whom
could bring the head of
the president

Wishing to eliminate a
sign or symptom of a
disease
Giving an expensive
drug & polypharmacy
Increasing ADRs &
iatrogenic disease
Spending a lot of
money
But it cloud be then
overcome by the
cheapest drug

Dangerous doctors
doctors are
the third leading
cause of death in the US,
causing 250,000 deaths
every year
http://www.mercola.com/2000/jul/30/doctors_death.htm

Doctors versus Guns in the U.S,1999

Some Startling Statistics
http://www.concealcarry.org/DangerousDoctors.htm

Parameter

Doctors

Gun
Owners

Number of person

700,000

80,000,000

Accidental
deaths/year

120,000

1,500

Accidental deaths per

(doctor) or (gun owner)

0.171

0.0000188

doctors are approximately

9,000 times more dangerous than gun owners

the number of people who die

as a result of:

Medical mistakes kill almost 100,000

Accidents/adverse effects (96,000),
Pneumonia and influenza (86,000),
Diabetes (63,000),
Suicide (31,000), or
Kidney disease (25,000) - and
certainly far more than in automobile
accidents, as the result of homicide or other
crimes, AIDS, etc.
http://ash.org/dangerous-doctors.html

Who is the dangerous doctor?

Does not know that he or she knows nothing
Looks like knowing everything, but knows a few
only
Does not know how to manage the patient
properly, rational prescription (i.e, polypharmacy)

Does not cure the disease but create the new

illness (iatrogenic disease)
Does not treat the patients but referring them to
be buried, (i.e., careless in the safety of medicine)
Always worse the patients emotion & pocket

Unethical professional behavior, not fit to

work as a doctor, etc

how to find them before they kill you!

How does someone become

a dangerous doctor?
drug companies greatly influence doctors
prescribing habits
family doctors are more likely to rely on
information supplied by drug manufacturers
rather than on information from independent
sources
About 70 percent of GPs regarded drug
representatives as an efficient way to obtain
new drug information
information may be misleading, biased or
inaccurate
Family Practice January 20:61-8,2003

Who is the dangerous doctor?

Someone who :
always prescribe dangerous drug
an agent with various adverse effects
does not care to:
the condition of patient treated
the indication of drug prescribed
the safety of drug administered
the kinetics of drug administered
the cost of drug administered
the drug interaction
the correct and clear drug prescription

always prescribe dangerous drug

Adverse drug reaction surveillance in pediatric
and adult patients in an emergency room
Munoz et al. Med Clin (Barc) 111(3):92-8,1998

Drugs

Children

Adults

NSAID

10.4%

28.2%

CV drugs

15.9%

Antimicrobials

49.5%

14.5%

GIT drugs

11.1%

Respiratory drugs

19.9%

Vaccines

9.2%

NSAID ADR-related hospitalizations

Cooper JW. South Med J 92(5):485-90,1999

do not care .
to the condition of patient treated
Age (children, elderly, nursing women)
Concomitance diseases
Polypharmacy
Many doctors involved
Children are not adults in small size
Elderly always have pharmacological
problems
Prescribing Cascade is the common
cause of polypharmacy in elderly

Critical approaches
in selecting medicines
Adverse
reaction
NNH

Therapeutic
NNT
effect
GREATEST Maximal
Minimal
SMALLEST
(> 100)

SMALLEST
(2-4)

Maximal
GREATEST
Minimal

Yes
?

?
No

There are two reasons to withdraw from the treatment either

no efficacy (NNT very high) or
serious adverse reactions (NNH very low).

discontinuation rate (%)

Withdrawal (%)

55%

23%

Henti terapi
karena
tidak
merasakan
efek terapi

19 %

9%
2.3 %

0.7 %

Henti terapi
karena
merasakan
efek samping

number needed to treat (NNT) for at least 50%

pain relief over 4-6 hours in patients with
moderate to severe pain, all oral analgesics
except morphine, pethidine and ketorolac

Principles of Analgesic Prescribing

WHO Analgesic Ladder

Strong opioid
NSAID
adjuvant analgesic
NSAID
adjuvant analgesic
weak opioid
(codeine)
paracetamol
or NSAID
adjuvant analgesic
Pain threshold

mild

Pain tolerance

moderate

severe

10

Pharmacologic Agents
Affect Pain Differently
Inhibition of
Ascending
Pain Pathways
Opioids

PNS

Peripheral
Sensitization

BRAIN

Descending Modulation
CNS

Spinal
Cord

Dorsal
Horn
NSAIDs
Antiarrhythmic
Local Anesthetics
Topical Analgesics
Anticonvulsants
Tricyclic Antidepressants
Opioids

Anticonvulsants
Opioids
Tricyclic/SNRI Antidepressants

Central Sensitization
Alpha-2 Delta agonists
Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Tricyclic/SNRI Antidepressants

Acute vs Chronic Pain

Drug
Duration of
pain

Component

Acute

Chronic

Rapid onset

Long duration

Short, self limiting, Persists after healing,

well-characterized
3 months

Nociceptive

Nociceptive
Neuropathic

Mild vs Severe Pain

Drug

Mild

Severe

Low dose

High dose
Potent agent

Etoricoxib, a long half-life (22 hours):

dosage and efficacy
Pain
Dose
Note
indications
(mg)
Chronic pain
OA
30 60 Curtis SP, et.al.
2005

Acute pain
Gouty arthritis
Dysmenorrhea

120

120

Maximum 8
days
Maximum 8

Acute Pain Severe Pain

How to change the onset of

action of the long half-life NSAID
Concentration

NSAID long half life

Acute

o
r
long duration e
but slow onset ng
a
D
increased
By increasing the dose ???:
?
onset!becomes earlier
the dose
c
i
but adverse effects enhanced
h
t
E
Effective concentration
?
e
v
Sa
?
l
a
Time
n
o
i
t
Slowly

Chronic
a
R

do not care .
to the safety of drug administered
The safety of drug administered depend on:
Type of drug
Pharmacodynamic
Higher dose, greater effect but more toxic

Pharmacokinetic
The shortest half-life, the safest drug

Clinical condition
Severe condition, high risk for adverse effects

Duration of administration

do not care .
to the safety of drug administered

The only ADR of

NSAID is GI event ?

Evolution in arthritis management: focus on COX-2 inhibitors

Carlos Valdes, PharmD, BCPS. Clinical Science Manager. Pharmacia Co.
April 14, 2002

The 10 leading causes of death

as a percentage of all deaths
in the United States, 1990 and 1996
1990

1996

Source: CDC, National Center for Health Statistics

WHO Statistical Information System (WHOSIS)

Numbers and rates (per-100.000) of
registered deaths
United States of America - 2000

No

Cause

Rate

CVS

941.524

668.5

Malignancy

553.091

393.4

Respiratory disease

186.346

132.5

Gastrointestinal disease

84.015

58.8

Accidents

73.785

55.1

Diabetes Mellitus

69.301

49.2

Infectious & Parasitic disease

69.007

42.0

Skin & Subcutaneous tissue disease

3.753

2.6

Drug, medicaments causing adverse

effects in therapeutic use

2.059

2.1

Ulcer of stomach and duodenum

4.504

3.2

The Implications of NSAID

Selectivity
Cardiovascular Risk

Gastrointestinal Risk

Thrombosis,
Myocardial Infarction

Bleeding Ulcer
Complications

Discontinuation

Discontinuation

Et
or
ic
Ro oxi
b
fe
co
xi
b
C
Di ele
cl c
of ox
en ib
ac
Ib
up
ro
fe
n
Na
pr
ox
en

Blood Pressure
Increase

COX-2

COX-1

Degree of Selectivity
Adapted from Antman EM, et al. Circulation. 2007;115:1634-

Celecoxib vs Etoricoxib
CV & Renal Safety Profile

Blood pressure change

Zhang J et al. JAMA 2006;296:1619-32; Schwartz JI et al. J Clin Pharmacol 2007;47:1521-31

Lowest GI risk

NSAID GI
Toxicity
generally
varies
with halflife of
the
agent

Shortest half-life

NSAID

Diclofenac

Naproxen

Piroxicam

Dose (mg/d)

100

750

20

Half-life (hr)

1.5

14

50

24 hr fecal blood
loss (mL)

0.53 +/- 0.21

2.76 +/- 2.22

1.16 +/- 0.62

Henry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med

Risk Factors of
Ulcer Complications from NSAIDs

Relative risk

incidence of ulcer (%)

Number of Risk Factors &

Incidence of Ulcer Complications
NNH 5

NNH 12
NNH 50
NNH 125

Silverstein FE. Ann Intern Med 1995;123:241-9

Adverse Effects of NSAIDs

Ototoxic

Bronchospam

Hepatotoxic

Bleeding

Allergy

Color blindness

CHF

UGIB
UGIB
Nephrotoxic

Tocolytic

Mechanism of = Mechanism of
therapeutic effects
adverse effects

Kaskade peresepan di klinik pribadi

Keadaan awal

Nyeri
dengkul

terapi

AINS

Simtom baru

Nyeri
ulu hati

terapi ikutan

antasida

konstipasi
laksansia
diare

dst

rematologis
serangan
GOUT

AINS
PSMBA
gastroenterologis

hidro
klorotiazida

Hipertensi

misoprostol

diare . . . . .

IATROGENIK
(iatro = dokter)

PAIN
NSAID

fluid
retention

increase
BP

diuretic

Anti-

hypertension

PUB

heart
burn

misoprostol

antacid

Prescribing
Prescribing Cascade
Cascade

PAIN
CANCER

ALZHEIMER
DISEASE

NSAID=Rp

fluid
retention

increase
BP

PUB

heart
burn

Rp

Rp

Rp

Rp

Iatrogenic Cost

do not
care ..
COMPARATIVE
COSTS for 28 DAYS THERAPY
(in , spent by the General Medical Services on NSAID in 1999)
to the cost of drug administered
DICLO 50 mg TDS +
Lansoprazol 15 mg OD
DICLO/MISO 75 mg BD
NIMESULIDE 200 mg BD
NIMESULIDE 100 mg BD
MELOXICAM 15 mg OD
MELOXICAM 7.5 mg OD
ROFECOXIB 25 mg OD
ROFECOXIB 12.5 mg OD
CELECOXIB 400 mg OD
CELECOXIB 200 mg OD
DICLOFENAC 50 mg TDS
IBUPROFEN 800 mg TDS

Pain in risky population

PATIENT GROUP

PREDICTABLE
PROBLEMS

Babies & Infants

Elderly

Communication; drug handling

Coexisting illness; drug
handling

Respiratory
disease

Respiratory depression;
NSAIDs & asthma

Renal Failure
Drug handling; NSAIDs
Pregnant women Early closure of ductus
arteriosus

do not care .
to the kinetics of drug administered

Drug accumulation
3x11x3
Efek terapeutik Efek samping obat
Choose the shortest half-life

do not care .
to the correct and clear drug
prescription

CELEXA for CELEBREX?

A Case of Medication Sample Error
Moyer B, Shrading W, Burkhart KK
Int J Med Toxicol 3(2):7,2000

citalopram (Celexa). a selective serotonin (5-HT) reuptake inhibitor

Illegible handwriting
imagine having to read this !

Captopril 25mg
#60
Tab i BID

do not care .
to the drug interaction
NSAID + antihypertensive agent
Morgan & Anderson. J Clin Hypertens 5(1):53-7,2003
indomethacin worsened the antihypertensive effect of enalapril

Bhagat K. East Afr Med J 78(10):507-9,2001

diclofenac, ibuprofen or sulindac did not neutralise the
antihypertensive effect of lisinopril

Graves & Hunder J Clin Hypertens 2(6):396-8,2000

worsening of hypertension by COX-2 Inhibitors

Kurata et al. Jpn Circ J 63(12):1002-3,1999

syncope caused by NSAID loxoprofen and ACE-inhibitor
imidapril

Hay et al. J Emerg Med 22(4):349-52,2002

fatal hyperkalemia related to combined therapy with a COX-2
inhibitor rofecoxib, ACE inhibitor enalapril

Used PLACEBO
NSAID is the only analgesic
long- half-life analgesic for an acute pain
High dose analgesic is the savest
Dont care to:
Patient condition
Pharmacokinetic
Drug interaction
Cost

Be a smart
doctor
and the right
one too

KEBANGGAAN INDONESIA UNTUK

DUNIA