CURRICULUM VITAE
Nama : dr. Dewi Selvina Rosdiana, M.Kes
TTL : Jakarta, 8 Mei 1979
Alamat : Jalan Mangga I No. 215B Rt. 003 / Rw. 005
Kel. Utan Kayu Utara, Kec. Matraman,
Jakarta Timur Kode Pos : 13120
E-mail :
[email protected]Riwayat Pendidikan
2004 Profesi Dokter di Fakultas Kedokteran Universitas Padjajaran Bandung
2005 Magister Farmakologi di Fakultas Kedokteran UNPAD Bandung
Riwayat Pekerjaan
Jan 2006 ~ ... Staf Pengajar, Departemen Farmakologi dan Terapeutik FKUI
Mar 2006 ~ ... Anggota Panitia Penilai Obat Jadi Divisi Efikasi dan Keamanan Obat, BPOM
GERIATRIC PHARMACOLOGY
Dewi Selvina Rosdiana
Department of Pharmacology & Therapeutics
Faculty of Medicine Universitas Indonesia
2 DEKADE FKUP97 − 11 Nov 2017
Epidemiology of Drug Use in The Elderly
• Elderly population (> 65 yrs) represents approx. 13% of total
population, but purchase 33% of all prescription drugs
• Consume 40% of OTCs
• Fastest growing population in the US
• By 2040, estimated they will represent 25% of total population
and will buy 50% of all prescription drugs
• 20% of geriatric hospitalizations are due to medications
problems
Epidemiology of Drug Use in The Elderly
• Geriatric patients receive + 12 Rx/year compared to only
5/year for those < 45 yrs.
• More drugs are available each year, but most have not been
clinically evaluated in those 70 yrs of age and none for those
over 85 yrs !!!
• Knowledge of drug-drug interactions has expanded and the
doctors are responsible for knowing and calculating these
effects
• Physicians should concern about the risk of adverse drug
reactions, but this should not lead to under-treatment
OUTLINES
Pharmacologic changes associated with aging
• Pharmacokinetics changes
• Pharmacodynamics changes
Principles of prescribing for older patients
Polypharmacy
Physiologic changes with aging
Physiologic changes with aging
Physiologic changes with aging
Physiologic changes with aging
Pharmacokinetics
Processes of Pharmacokinetics:
• Absorption
• Distribution
• Metabolism
• Elimination
Absorption
= The movement of drug from the site of administration into the blood
stream
The major site of absorption : small intestine, surface area of abs. :
200 m2 (280 cm long, 4 cm Ø , villi, microvilli)
Methods of absorption:
- Passive diffusion
- Active transport
- Facilitated diffusion
Absorption
Rate of absorption is influenced by:
• pH (degree of ionization)
• Solubility of drug
• Surface area of absorption
• Blood flow
• Molecular weight
• GI tract motility
Effects of Aging on Absorption
• Gastric acid production declines → increased gastric pH
May alter the lipid solubility of some drugs and alter rate of
absorption
• Decreased GI motility → Longer gastric emptyng
Increase absorption of acidic drugs
Delay or reduce absorption of basic drugs
• Decreased intestinal blood flow
Delay absorption
Effects of Aging on Absorption
• Cmax may be altered, (generally toward lower levels) and
delayed due to decreased mobility and decreased gastric
blood flow but generally not clinically significant
• Exceptions: drugs with extensive first-pass metabolism,
bioavailability may increase (theophylline, digoxin, warfarin,
b-blockers, Ca-antagonists, etc)
• Overall: Bioavailability is usually not dramatically changed in
most patients as a result of aging
Distribution
• Distribution of drugs is much depends on body composition
Young Adults Geriatrics
Body water 61% 53%
Lean body mass 19% 12%
Body fat 26-33% (women); 38-45% (women);
18-20% (men) 36-38% (men)
Serum albumin 4.7 g/dL 3.8 g/dL
Concept of Volume of Distribution
• Calculated based on plasma concentration
FD F = bioavailability;
Vd = D = drug dose;
C C = plasma conc.
• High C
the Vd is small the drug is concentrated in blood
• Low C
the Vd is large extensively distributed in the body
or accumulated in tissues
Volume of Distribution
Examples :
Total real blood volume of adult: 3.5-5 L
Vd of phenylbutazone = 0.1 L/kg = 5 L/50 kg
concentrated in blood
Vd of caffeine = 0.6 l/kg = 36 L/50 kg
distributed in total body water
Vd of digoxin = 7 l/kg = 350 L/50 kg
accumulated in tissues
Effects of Aging on Volume Distribution
• Body water
• Lower VD, but increase concentration of hydrophilic drugs such as
vancomycin, lithium, aminoglycoside, cephalosporins, alcohol
• Lean body mass
• Lower VD, but increase concentration of drugs that bind to muscle
or other proteins (digoxin)
• Fat stores
• higher VD but lower concentration of lipophilic drugs such as
benzodiazepines
• Prolong action of lipophilic drugs (anestethics, CNS drugs)
Effects of Aging on Plasma Protein
• plasma protein (albumin) increased unbound (active) drug
• Influence of low albumin state may be significant if:
– Severe hypoalbuminemia
– High protein binding drug (>85%)
– Narrow margin of safety
• In the majority of the elderly, serum albumin levels are not
altered in the absence of advanced chronic disease or severe
malnutrition.
Protein Binding Displacement Interaction
• Drugs with similar physicochemical properties can compete each
other
• These interactions are clinically important if:
The displaced drugs fulfill 3 criteria :
- high plasma protein binding : > 85%
- small Vd : < 0.15 l/kg (acidic drugs)
- narrow margin of safety
A prerequisite for a displacer drug :
- its conc. is high enough to begin saturating its own binding sites,
- eg. phenylbutazone, salicylic acid, valproic acid and sulfonamides
Protein Binding Displacement Interaction
Example :
Phenylbutazone : a displacer for albumin site I
Warfarin (displaced drug): protein binding 99%, Vd 0.14 l/kg
Phenylbutazone will displace warfarin from albumin free
warfarin hemorrhage
Tolbutamide (displaced drug): protein binding 96%, Vd 0.12 l/kg
Phenylbutazone will displace tolbutamide from albumin
free tolbutamide hypoglycemia
Metabolism
• Aim of metabolism: to convert lipid soluble drugs to water soluble
(more polar) compounds can be excreted via kidneys or bile
• 2 phases of drug metabolism:
PHASE I: oxidation, reduction, hydrolysis
• drugs become inactive, less / more active, or toxic
• drugs obtain polar groups (-OH, -NH2, -COOH, SH) can react with
endogenous substrates in phase II reactions
PHASE II : conjugation
• Conjugation with endogenous substrates (glucuronic acid, sulphate,
acetyl, glutathion)
• Drugs almost always become inactive
Metabolism
• Most important : oxidation by cytochrome P450 (CYP) in liver
microsomes
• + 50 CYP isoenzymes are functionally active in human
• Major CYPs for drug metabolism :
- CYP3A4/5 - metabolyzed > 50% drugs for human
- also expressed in intestinal epith. and kidney
- CYP2D6 - the first known (debrisoquine hydroxylase)
- CYP2C9, CYP2C19
- CYP1A2 - previously known as cytochrome P448
- CYP2E1
Effects of Aging on Drug Metabolism
• liver mass, hepatic blood flow, and enzyme activity
– Delayed/reduced metabolism of drugs
– Reduced first pass metabolism
Higher plasma levels risk of intoxication
• Other factors: chronic disease, impaired homeostasis, may
have more effect than aging itself
• The greatest changes are in phase I metabolism
• Much smaller changes in phase II reactions
Effects of Age on hepatic clearance of some drugs
Elimination
Most drugs exit body via kidney
There is a linear reduction in renal functions with
aging in most patients, although not all.
Aging and common geriatric disorders can impaire
kidney function
• Leads to drug accumulation and toxicity if not monitored,
• especially for drugs that are excreted in active form such as
digoxin, lithium, aminoglycosides, vancomycin etc.
Effects of Aging on Drug Elimination
• kidney size
• renal blood flow
• number of functioning nephrons
• renal tubular secretion
• Results: Lower glomerular filtration rate
– Longer half-life of medications
– Increased side effects
– Increased potential for toxicity
Effects of Aging on Drug Elimination
The estimation of creatinine clearance
a useful screening approximation for dosage adjustments
• Cockroft-Gault formula
(applicable to patients from ages 40 through 80)
• Online calculators MDRD (Modification of Diet in Renal
Disease) formula
Drug highly dependent on renal function for elimination
Age-related changes in drug Pharmacokinetics
Effects of Aging on Pharmacodynamics
• The Impact of Aging on pharmacodynamics
– Higher sensitivity of receptors to CNS drugs
– Decreased homestasis risk of orthostatic hypotension in response to
antihypertensives
– Multipathology polypharmacy drug interaction
– Benzodiazepines may cause more sedation and poorer psychomotor
performance in older adults.
– morphine produces longer pain relief but danger is increased for
respiratory depression
Effects of Aging on Pharmacodynamics
• Prolonged half life and decreased
elimination are associated with increased
risk of adverse drug reactions in the
elderly
• Improper dosing is a bigger risk factor in
the elderly.
• General Rule: Start Low and Go Slow!!!
Adverse Drug Reaction in The Elderly
• Age related physiologic decline, increased chronic illness,
increased utilization of pharmaceutical compounds, all
must be considered.
• Absolute chronological age is less important than
physiological status in determining risk for ADR
• Some Adverse Drug Reaction in Geriatric Patients:
– Falls, dry mouth, constipation, blurred vision, confusion,
hypotension, muscle cramps, impotency, weakness can be due to
anticholinergic compounds, diuretics, antiarrythmitics,
antipsychotics etc.
Other Risk Factors for ADR in The Elderly
• Functional impairments
– Vision loss
– Cognitive dysfunction
– Musculoskeletal disorders
• Socio cultural factors may make person unable/unwilling to
follow prescribed medical regimen
• Loss of family, friends, income
• Limited/fixed income
• Economic factors
– May have to choose between food and medications
Other Risk Factors for ADR in The Elderly
• Economic factors
– May have to choose between food and
medications
• OTCs instead of expensive doctor visits
• Use of outdated medications
• Use of home remedies
• Share medications
• Nutritional status may affect how body metabolizes
medications
Polypharmacy
• Concurrent use of multiple medications
• Elderly rely on various medication to
control or relieve a range of age-related
problems
– Cardiovascular disease
– Diabetes
– Degenerative joint disease
– Autoimmune disorders
Polypharmacy
• Risks of problems:
– Medication errors
• Wrong drug, time, route
– Adverse effects from each drug
• Polypharmacy primary reason for adverse
reactions
– Adverse interactions between drugs
Principles of Prescribing for Elderly
• Evaluate the need of drug therapy
• Take a careful drug history
• Know the pharmacology of the drug prescribed
• Define the goal of drug therapy
Start low and advance dosage slowly
• Simplify the therapeutic regimen as much as possible.
• Regularly review the treatment plan, and discontinue drugs no
longer needed
Principles of Prescribing for Elderly
• If possible, avoid prescribing an additional drug to treat an
adverse drug event.
• Adverse effects are frequently dose related so adjust dose!!
– Discontinue or lower the dosage of the compounds that the patient is
taking first before adding more compounds.
• Have a high index of suspicion that this new condition may be
iatrogenic induced!
• Any new symptom or condition in an elderly patient should be
considered a drug side effect until proven differently!!!
REFERENCES
• Katzung BG. Special aspects of geriatric pharmacology. In Katzung BG, eds. Basic
& Clinical Pharmacology. 13th ed. Singapore: McGraw-Hill; 2015.p.1024-32
• Vestal RE, Gurwitz JH. Geriatric pharmacology. In Carruthers SG, eds. Melmon
and Morrelli’s Clinical Pharmacology. Basic principles in therapeutics. 4th ed. USA:
McGraw-Hill; 2000.p.1151-77
• Grahame-Smith DG, Aronson JK. Drug therapy in young and old people. Oxford
textbook of clinical pharmacology and drug therapy. 3rd ed. New york: Oxford
university Press; 2002.p.119-26.
• Williams BR. Geriatric Therapy. In Koda-Kimble MA, eds. Applied Therapeutics:
The clinical use of drugs. 9th ed. Baltimore: Wolters Kluwer-Lippincott Williams &
Wilkins; 2009. p. 99-199-22
• Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s. The pharmacological
Basis of therapeutics. 12th ed. New york: McGrawHill; 2011.p. 1571-92
• Emily R. Hajjar; Shelly L. Gray; Patricia W. Slattum Jr; Lauren R. Hersh; Jennifer
G. Naples; Joseph T. Hanlon. Geriatrics.
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