OBAT PADA MANULA

Noor Wijayahadi
April 2007
Medications Most Commonly Used
in the Community

Analgesics
Diuretics
Cardiovascular
Sedative-hypnotics
Medications Most Commonly Used
in the Nursing Home
Antipsychotics
Sedative-hypnotics
Diuretics
Antihypertensives
Analgesics
Cardiovascular
Antibiotics
Manula  Resiko tinggi mengalami
efek merugikan dari obat
Faktor penderita
– Age-associated changes in pharmacokinetics
– Age-associated changes in pharmacodynamics
– Comorbidity: drug-disease interactions
– Polypharmacy: drug-drug interactions
– Kemampuan homeostasis berkurang
– Fungsi organ berkurang
Faktor sistem layanan medik
– Fragmentation of care (Poly-doctoring)
– Inadequate training in principles of geriatric practice
Therapeutic Response

Therapeutic Window

Toxic Response

Age
 “The Precipice”

Physiologic
Reserves
Available
Physiologic
Reserves
Already In Use

Increasing Age
 Masalah Utama
Pilihan obat atau dosis yang tidak tepat
Concomitant disease  affect metabolism
of or response to drug
Polypharmacy  drug - drug interactions
Patient behavioural factors
Perubahan PHARMACOKINETICS
Absorption
active transfer
Body composition
lean body mass
body fat
plasma albumin
Liver metabolism
oxidation / microsomal enzymes
Renal clearance
 Perubahan
PHARMACODYNAMICS
Brain sensitivity  Benzodiazepines and
narcotic analgesics more effective

Coagulation mechanism control

 Anticoagulants more potent

Adrenergic receptor sensitivity

 B-blockers less effective

Penurunan fungsi homeostasis

Baroreceptor sensitivity
postural hypotension

Thermoregulation
hypothermia
COMMON PITFALLS 1 :
Gagal mengobati kondisi yang seharusnya
bisa diobati (treatable conditions)

Thrombolytic therapy
the older the patient, the greater the benefit
the older the patient, the less likely to be
thrombolysed
Hypertension
30 - 40% decrease in risk of CVA if ISH treated
 BLOOD PRESSURE AND AGE

160
140
120
100
80
60
40
20
0
30 40 50 60 70 80
COMMON PITFALLS 2 :
Prescribing for symptom and not for
diagnosis

“ A pill for every ill ”

NEW HYPNOTIC PRESCRIPTIONS
(per percentage patient pop. per yr.)

4 Male 0-65
3 Female 0-65
Male >65
2 Female >65
1

0
1987 1989
PRESCRIPTIONS BY AGE
(Items per person per year)

40
35
30
25
20
15
10
5
0
42 46 50 54 58 62 66 70 74 78 82 86 90
 EFFECTIVE PRESCRIBING 1
Utamakan non-pharmalogical treatment
modify diet
stop smoking, reduce alcohol
physical exercise
walking aids, household adaptations
social supports
 EFFECTIVE PRESCRIBING 2
Treat conditions in order of priority
Pertimbangkan kegagalan fungsi organ
Start low  mulai dosis kecil , naikkan
dengan hati-hati
Gunakan formularium yang terbatas
Monitor compliance and response
Review pemakaian obat secara reguler
Ikut sertakan PENDERITA
Who Takes the Most Medications?
Women
Individuals with
multiple health
conditions
Frail elderly
Nursing home
residents
Medications Most Commonly Used
in the Community

Analgesics
Diuretics
Cardiovascular
Sedative-hypnotics
 Umur mempengaruhi
metabolisme obat?
Pada manula:
– Slower organ function
– Slower blood circulation
– Increased body fat
 obat bertahan lama di dalam tubuh 
resiko terkena efek samping obat
meningkat
 Age-Related Changes:

Total body water menurun  konsentrasi dalam

darah obat yang larut-air meningkat
Perubahan berat badan  mempengaruhi dosis
yang diperlukan dan lama obat dalam tubuh:
– More body fat  prolonged half-life
– Less lean body mass  increased drug concentration
Perubahan sistem pencernaan 
mempengaruhi kecepatan absorbsi obat 
onset obat lebih lama
 Age-Related Changes:

Slower circulation  delay drugs getting

to liver and kidneys
Slow down of liver and kidneys  affects
time it takes for medication to break down
and leave body
Less absorption from transdermal patches
Drug “receptor” sites may be different in
older adults
 Changes in Pharmacokinetics
Perubahan fisiologis dan fungsi organ pada
manula  perubahan Farmakokinetik
Pharmacokinetics is the time course of a drug
and its metabolites through the body
– Absorption
– Distribution
– Clearance: elimination (renal), metabolism (liver)

2004: Cusack, Amer. J of Geriatric Pharmacotherapy

 Volume of Distribution (Vd)
Proporsi lemak meningkat dan volume otot
berkurang  merubah Vd
Vd obat larut lemak (fat soluble drug)
meningkat  waktu paro meningkat:
diazepam, thiopental, trazadone
Vd obat larut air (water soluble drug)
menurun  kadar obat dalam plasma
meningkat: ethanol, lithium,
aminoglycosides, alcohol, digoxin
 Protein Binding
albumin berkurang  chronic disease:
e.g.,malnutrition, liver or kidney conditions.
obat dengan ikatan protein tinggi  kadar
obat bebas meningkat.
 ceftriaxone,diazepam, phenytoin,
warfarin.
 Eliminasi Obat menurun

Fungsi ginjal menurun  eliminasi oleh ginjal

berkurang.
Even in the absence of kidney disease renal clearance
may be reduced 35-50%.
 therapeutic effect dan resiko toksisitas meningkat
 perlu pengurangan dosis atau perubahan interval
pemberian obat.
 Metabolisme hepar berkurang

•Phase I, terutama reaksi oksidatif  menurun

•Phase II, terutama reaksi konjugasi relatif tidak

berubah.

diazepam is metabolized via Phase I reactions in the

liver, at least initially.
 Drugs with Cytochrome P450 Effects
(partial)
Inhibitors Inducers
Allopurinol Metronidazole Barbiturates
Amiodorone Quinolones Carbamazepine
Azole antifungals Phenytoin
Cimetidine Rifampin
INH Tobacco
SSRIs
Tacrine
 Hepatic Metabolism
Decreased liver size and hepatic blood flow.
Regional blood flow to the liver at age 65 is reduce
by 40-45% compared to a 25 year old.
Metabolic clearance of drugs by the liver may be
reduced.
Disease effects: liver congestion from heart failure
decreases warfarin metabolism and an increased
pharmacologic response.
Environmental effects: smoking stimulates
monoxygenase enzymes and increases clearance
of theophylline.
 Changes in Pharmacodynamics
Older patients may have more sedation and
impaired function after a single dose of
benzodiazepines than younger persons.
After single dose of nitrazepam older patients
made more mistakes on psychomotor testing
compared to placebo while younger patients
had no impairment .
 Suboptimal Quality
Typology of Quality Problems:
– Overuse (Polypharmacy)
– Underuse
– Misuse (Inappropriate Prescribing)
– Errors
 Suboptimal Prescribing
Polypharmacy
Underuse of Effective Medications
Drug-Drug Interactions
Drug-Disease Interactions
Inadequate Monitoring
Inappropriate Dosing
Inappropriate Duration
Drugs to Avoid
 Drug-Drug Interactions
Penyebab tersering ESO pada manula
Jumlahnya sangat banyak  Almost
countless  peresepan elektronik
Some common examples
– Statins and erythromycin and other antibiotics
– TCAs and clonidine or type 1Anti-arrythmics
– Warfarin and multiple drugs
– ACE inhibitors increase hypoglycemic effect of
sulfonylureas
 Drug-disease Interactions

Patient with PD have increased risk of drug

induced confusion
NSAIA (and COX-2’s) s can exacerbate CHF
Urinary retention in BPH patients on
decongestants or anticholinergics
Constipation worsened by calcium,
ahticholinergics, calcium channel blockers
Neuroleptics and quinolones lower seizure
thresholds
 Polypharmacy
Polypharmacy = pemberian banyak
obat melebihi indikasi penggunaan
59% manula mendapat obat tanpa
indikasi yang jelas.
55% manula mendapat obat tanpa
indikasi, 32.7% mendapat obat yang
tidak efektif, 16.8% mendapat obat
duplikasi
2001: Hanlon, JAGS
 Underuse
Among patients elderly patients with
cardiovascular disease and diabetes, only
19.1% of patients were prescribed statins. In
patients 66 to 74 years old, the adjusted
probabilities of statin prescription were 37.7%,
26.7%, and 23.4% in the categories of low,
intermediate, and high baseline risk,
respectively.

The likelihood of statin prescription was 6.4%

lower (adjusted odds ratio, 0.94; 95%
confidence interval, 0.93-0.95) for each year of
increase in age and each 1% increase in
2004: Ko, JAMA3-year mortality risk.
predicted
 Inappropriate Prescribing

20-27% manula mendapat resep yang

tidak diperlukan (inappropriate).
Inappropriate prescribing meningkatkan
resiko jatuh, fraktur femur, cognitive
impairment, diminished independence,
dan mortalitas
inappropriate drug prescribing to
the elderly?
The Beers List .
a list of medications identified by an expert
panel as being inappropriate for older
persons because of ineffectiveness or
because they pose a high risk for adverse
drug events.
Beers MH Arch Intern Med 1997
 The Beers List
The Beers List, berisi 33 obat dalam 3
kategori:
1. Drugs that should always be avoided .

2. Drugs that are rarely appropriate.

3. Drugs with some indications , but that are often

misused.

Zhan et al. JAMA 2001

 Drugs And Dosages to Avoid

Meperidine
Diphenhydramine
The most anticholinergic tricyclics:
amitryptiline, doxepin, imipramine
Long acting benzodiazepines such as
diazepam
Long acting NSAIDs such as piroxicam
High dose thiazides (>25mg)
Iron: 325 mg once daily is enough
11 drugs that should always be
avoided in the elderly:
Barbiturates
Belladonna alkaloids
Chlorpropamide
Dicyclomine
Flurazepam
Hyoscyamine
Meperidine
Propantheline
Meprobamate
Trimethobenzamide
Pentazocine

Zhan et al. JAMA 2001

 Tangga Peresepan
(Prescribing Cascade)

The prescribing cascade

terjadi bila satu obat Drug 1
diresepkan,
Menyebabkan timbulnya
efek samping obat / ADE
adverse drug event (ADE),

Mendorong peresepan obat Drug 2

kedua untuk mengatasi ESO
sebelumnya
Rochon PA et al, BMJ 1997
 The Prescribing Cascade
There are numerous examples of the prescribing cascade in the
medical literature.
For example, it has been observed that patients prescribed
metoclopramide ( a gastric motility agent) are more likely to be
initiated on treatments generally reserved for the management of
idiopathic Parkinson’s Disease (e.g. Drugs containing Levodopa).

Metoclopramide
In this case, metoclopramide use
can lead to extrapyramidal
symptoms, which may be Extrapyramidal Effects
misdiagnosed as Parkinson’s
Disease.
Levodopa Rx
Avorn J et al, JAMA 1995
 The Prescribing Cascade
Another example relates to the fact that older persons who have
been prescribed NSAIDs appear to be at increased risk for being
initiated on antihypertensive therapy.
NSAID Rx

In this case, NSAID use

increases blood pressure Blood Pressure
leading to the need for blood
pressure lowering therapy.
Antihypertensive Rx

In both examples, the initiation of new drug treatments in older persons

could have been avoided if there was recognition of the risks of certain
drug treatments (e.g. metoclopramide and NSAIDs) in elderly patients.
Gurwitz JH et al, JAMA 1994
 The “Prescribing Cascade”

Penyebab utama polypharmacy pada

manula
Some common examples
– NSAID ->HTN->antihypertensive therapy
– Metoclopromide ->Parkinsonism ->Sinemet
– Dihydropyridine -> edema ->furosemide
– NSAIA ->H2 blocker ->delirium ->haldol
– HCTZ ->gout->NSAIA ->2nd antihypertensive
– Sudafed ->urinary retention ->alpha blocker
– Antipsychotic ->akithesia ->more meds
NSAID (Anti-inflamasi non-steroid)

Efektifitas Parasetamol = NSAIDs pada

osteoartritis ringan
NSAIDs side effects
– GI hemorrhage
– Decline in GFR
Decreased effectiveness of diuretics, anti-
hypertensive agents
Indication should justify the increased toxicity
of NSAIDs
Drugs and Cognitive Impairment

Anticholinergic drugs are common

offenders (TCAs, benadryl and other
antihistamines, many others)
Other offenders cimetidine, steroids,
NSAIAs
Medical Letter 2000 Drug Safety 1999 Drugs and Aging 1999
 Drugs and Falls

Biggest risk drugs are long acting benzodiazepines

and other sedative-hypnotics
Both SSRIs and TCAs associated with increased
risk of falling
Beta blockers NOT associated with increased risk
of falling in published literature
Mild increase in fall risk from diuretics, type 1A
anti-arrythmics, and digoxin
Leipzig, JAGS
 Drug-Food Interactions
Interactions between drugs and food
– warfarin and Vitamin K containing foods
(remember green tea, as well)
– Phenytoin & vitamin D metabolism
– Methotrexate and folate metabolism
Drug impact on appetite
– Digoxin may cause anorexia
– ACE inhibitors may alter taste
 Anticipate Side Effect
Narcotics
– Begin lactulose or sorbitol and a stimulant laxative
– Colace is NOT sufficient in most instances
Steroids
– Think about osteoporosis prevention
– Remember steroid induced diabetes
Levothyroxine
– Calcium interferes with absorption of levothyroxine
 Drug Discrepancies

Difference between medical record and

medication bottles in 76% of cases
– 51% of time medication not recorded
– 29% medication recorded that patient not
taking
– 20% dosage discrepancy
Risk Factors: Age, number of medications
– Bedell et al Arch Intern Med 160, 2000
 High Risk Situations
Patient seeing multiple providers
Patient on multiple drugs
Patient lives alone and/or has
cognitive impairment
Discharge from hospital or any
change in venue
Hospitalization: A High Risk Time

At hospitalization:
40% of admission medications stopped
45% of discharge medications were started
Serious prescribing problems in 22%
Other prescribing problems in 66%
– Beers JAGS 1989, Lipton Medical Care 1992
 Nonadherence
Lack of understanding of how to take
– High risk times: Hospital discharge, new meds
added, complex regimens
Unable to take
Conscious nonadherence
– Side effects
– Lack of understanding of benefits of drug
– Financial
 Complementary Therapies

Very commonly used in the elderly

Some common herbs and alternative therapies:
– “Anti-aging” DHEA, growth hormone
– Dementia Gingko biloba
– BPH Saw palmetto, PC-SPES
– OA Chondroiton sulfate,
glucosamine
– Depression St. John’s wort, SAMe
 Adulterants in Products
California Department of Health
Services, Food and Drug Branch
– screened 250 Asian herbal products
– collected from herbal stores in California
– assayed products using gas chromatography,
mass spectrometry, and atomic-absorption
techniques
– Ko, NEJM 1998; 339; 847
32% contained unlabeled medications,
14% mercury, 14% arsenic, 10% lead
 Herbals and Supplements:
Regulation
Demonstration of safety is NOT required prior to
marketing
Manufacturing standards are not required
Can have health claims, but not claims about
treating, preventing, or curing
For glucosamine/chondroitin, on third of
combinations did not contain listed ingredient
www.consumerlabs.com has some drug
information
Herbals and Supplements:Potential
interactions with Rx Drugs
SAMe may increase homocysteine
levels
St. John’s wort and Oral contraceptives
Ginkgo may increase anticoagulant
effects of ASA, warfarin, NSAIAs,
ticlopidine, and may interact with MAOIs
Bottom line: Try to know what your
patient is taking, and ask in a
nonjudgmental way
 Prinsip Manajemen Obat
Riwayat pemakaian obat yang lengkap,
termasuk obat herba/tradisional/obat bebas
Hindari pemberian obat bila
keuntungan/benefit kecil , atau ada alternatif
pengobatan non-farmakologis
Pertimbangkan harga
Start low, go slow, but get there!
Buat cara pemberian yang sederhana
Tulis cara pemakaian sejelas mungkin
Minta penderita membawa seluruh obat yang
sedang diminum setiap kali periksa
 Principles (continued)
Pertimbangkan pemakaian kotak obat harian
atau “mediset”
Hentikan pemakaian obat yang tidak jelas
keuntungannya atau resiko efek sampingnya
lebih merugikan
Hati-hati pemakaian obat baru (newer drugs)
Hindari penggunaan obat > 5 macam 
Consider if the benefit of the 7th or 8th drug is
sufficient to justify the cost, increase in
complexity of regimen, and risk of side effects
 Newer drugs
What is unique about this compound?
What clinical data is available?
How does it compare with traditional
therapy?
How expensive is it?
With third party payers cover this
product?
Does the potential advantage of this new
drug justify the risk of using a new drug?
 The Message for Today
Start low

Go slow (but get to therapeutic levels)

Sometimes say no (how about other non-drug

treatments?)