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.)

6 5 4 3 2 1 0 1987 1989 Male 0-65 Female 0-65 Male >65 Female >65

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
Allopurinol Amiodorone Metronidazole Quinolones

Inducers
Barbiturates Carbamazepine

Azole antifungals
Cimetidine INH

Phenytoin
Rifampin 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-2s) 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 predicted 3-year mortality risk. 2004: Ko, JAMA

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 Chlorpropamide Flurazepam Meperidine Meprobamate Pentazocine

Belladonna alkaloids Dicyclomine Hyoscyamine Propantheline Trimethobenzamide

Zhan et al. JAMA 2001

Tangga Peresepan (Prescribing Cascade)

The prescribing cascade terjadi bila satu obat diresepkan, Drug 1

Menyebabkan timbulnya efek samping obat / adverse drug event (ADE), Mendorong peresepan obat kedua untuk mengatasi ESO sebelumnya

ADE

Drug 2

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 Parkinsons Disease (e.g. Drugs containing Levodopa). Metoclopramide In this case, metoclopramide use can lead to extrapyramidal symptoms, which may be misdiagnosed as Parkinsons Disease.

Extrapyramidal Effects

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 leading to the need for blood pressure lowering therapy.

Blood Pressure

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, antihypertensive 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 Dementia BPH OA DHEA, growth hormone Gingko biloba Saw palmetto, PC-SPES Chondroiton sulfate, glucosamine St. Johns wort, SAMe

Depression

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. Johns 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?)