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Geriatric Pharmacology

Nafrialdi

Why Geriatrics Pharmacology


is Important
Elderly population (> 65 yrs):
Constitute 13% of total population,
Purchase 33% of all prescription drugs
Consume 40% of OTCs
Elderly population is the fastest growing
population in the US
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Why Geriatrics Pharmacology


is Important
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
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Why Geriatrics Pharmacology


is Important
More new drugs are available each year
most have not been clinically evaluated in
those aged > 70 yrs
none for those over 85 yrs !!!

Geriatric patients receive + 12 Rx/year


compared to only 5/year for those < 45
yrs.
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Scope of Discussion
1. Effects of age on pharmacokinetics
2. Effects of age on pharmacodynamics
3. Polypharmacy
4. Principles of prescribing for older patients

1. EFFECTS OF AGE ON
PHARMACOKINETICS

PHARMACOKINETICS
What the Body Does to the Drug
Absorption
Distribution
Metabolism
Excretion

Absorption
Movement of drug from the site of administration
into the blood stream
How does absorption occur ?
1. Passive diffusion:

Absorption method for most drugs


Energy independent
Following concentration gradient

2. Active transport

Energy dependent
May opposite concentration gradient

3. Facilitated diffusion

Absorption
Small intestine: major site of absorption with
surface area of + 200 m2 . (280 cm long, 4 cm
, villi, microvilli)

Rate of absorption is influenced by:

pH (degree of ionization)
Presence of food/ other drugs
Solubility of drug
Surface area of absorption
Blood flow
Molecular weight
Bowel movement
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Absorption
Influence of pH (degree of ionization)
Weak acids :
HA H+ + A

Degree of ionization = [A-] / [HA] = [ion] / [non


ion] = 10 pH-pKa
Weak bases:
B + H+ BH+
Degree of ionization = [BH+] / [B] = [ion] / [non
ion] = 10 pKa-pH
Follows Henderson-Hasselbalch equation
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Ficks Law
Passive diffusion occur only for most unionized form
(usually lipid soluble), not for the ionized form (non lipid
soluble)

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Absorption
For a drug with pKa 4.4 and the pH of gastric
juice 1.4
Degree of ionization= 10 pH-pKa
= 10(1.4-4.4) = 10 -3 Unabsorbed
If the gastric pH is 3.4 (exp. In the presence of
antiacid drugs)

Degree of ionization:
= 101.4-3.4 = 10-1 unabsorbed
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Most drugs are weak electrolytes (weak


acids or weak bases)
Weak acid drug in acidic environment
(stomach) less ionized easily absorbed
Weak basic drug in the stomach highly
ionized less absorbed will be absorbed
in duodenum or intestine
Increase pH (by antiacid drugs/food)
reduces the absorption of acid drugs but
facilitate absorption of basic drugs.
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Reduced gastric acid production


Raises gastric pH
May alter solubility of certain drugs alter rate of
absorption

Reduced bowel movement


Delay or reduce absorption of basic drugs
Increase absorption of acidic drugs

Decreased blood flow


Delay absorption

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Other Factor that Affect Absorption


What is taken with the drug
Divalent cations (calcium, magnesium, iron)
can affect absorption of many
fluoroquinolones (e.g., ciprofloxacin)
Enteral feedings interfere with absorption of
some drugs
Drugs that affect GI motility can affect
absorption (hyoscamine, dicyclomine,
metoclopramide, cisapride, etc.).
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Overall:
Amount of absorption (bioavailability) is
usually not dramatically changed in most
patients as a result of aging
Exceptions
drugs with extensive first-pass
metabolism, bioavailability may increase
(theophylline, digoxin, warfin, b-blockers,
Ca-antagonists, etc).
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DISTRIBUTION
Distribution of drugs is much depends on body composition
Change of body composition change in Volume Distribution (Vd)

Young Adults

Geriatrics

Body water

61%

53%

Lean body mass

19%

12%

Body fat
Serum albumin

26-33 (women);
18-20 (men)
4.7 g/dL

38-45 (women);
36-38 (men)
3.8 g/dL
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Concept of Volume of Distribution


Calculated based on plasma concentration
Vd =

FD

(F = bioavailability; D = drug dose; C = plasma conc.)

C
High C small Vd the drug is concentrated in blood
Low C large Vd extensively distributed in the body
or accumulated in tissues

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Concept of 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
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Effect of Aging on Volume Distribution


Decreased body water
lower VD but increased concentration of
hydrophylic drugs ( vancomycin, lithium,
aminoglycoside, cephalosporins, alcohol )

Decreased lean body mass


lower VD, but increase concentration of drugs that
bind to muscle or other proteins (digoxin)

Increased fat stores


higher VD but lower concentration of lipophilic
drugs such as benzodiazepines
Prolong action of lipophilic drugs (anestethics,
CNS drugs)
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Plasma Proteins
In the blood: drug + protein forms drug-protein
complex and circulate throughout the body
Drug-protein complex dissociate very rapidly
(reversible binding) (t ~ 20 msec)
Only unbound drugs can diffuse into tissues:
To the sites of drug action drug effect
To the sites of drug binding (depot tissues)
To the sites of elimination : liver, kidney

Bound drugs are temporarily inactive and stay in


the blood
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Plasma Proteins
Albumin plays major role in drug binding
(it binds acidic drugs)
Other plasma protein:
Globulin:
CBG: corticosteroids binding globulin
SSBG : sex-steroid binding globulin
TBG: thyroxin binding globulin

1-acid glycoprotein: basic drugs


Lipoproteins: basic drugs
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Effects of Aging on Plasma Proteins


Influence of low albumin state may be
significant if:
Severe hypoalbuminemia
Drugs with high protein binding drug (>85%)
Drugs with narrow margin of safety

In the majority of the elderly, serum albumin


levels are not altered, except advanced
chronic disease or severe malnutrition.
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Protein Binding Displacement Interactions


Drugs w/ 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
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 for albumin binding
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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
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Influence of Age on Pharmacokinetics


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
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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
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Aging and Metabolism


Aging: decreased 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
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Interactions in drug metabolism (1)


Induction of metabolic enzymes :
enzyme synthesis rate of metabolism of drug
substrates tolerance
requires 3 days to 1 wk before max. effect is achieved

Inhibition of metab. enzymes : occur directly


directly conc. of drug substrates side effects/
intoxication
Recommandations:
dose of drug substrates, or
Do not be administered concomitantly (C.I.) if the
consequnce is dangerous
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Interactions in drug metabolism (2)


Example :
Terfenadine, astemizole, cisapride (substrates of CYP3A4)
are contraindicated with inhibitors (ketoconazole,
itraconazole, erythromycin, clarithromycin)
The interaction conc. of terfenadine, astemizole,
cisapride QTc interval (on ECG) ventricular
arrhythmias (torsades de pointes) death
Terfenadine : withdrawn in UK & USA (1998)
Astemizole : withdrawn worldwide (June 1999)
Cisapride : withdrawn worldwide (July 2000)

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1. Effect of Age on Pharmacokinetics


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
impair 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.
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Effects of Aging on Kidney Function


kidney size
renal blood flow
number of functioning nephrons
renal tubular secretion
Results: Lower glomerular filtration rate

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Key Concepts in Elimination


BUN and Serum Creatinine may not accurately
reflect true renal function in the elderly.
Inadequate protein intake may result in artificially
lowered BUN.
Diminished muscle mass or increased muscle loss
may result in lower creatinine and not altered renal
clearance.

In older persons, serum creatinine stays in


normal range, masking change in creatinine
clearance (CrCl)
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Serum creatinin may appear normal even when significant renal impairment exists.
Cr clearance=(140-age)(IBW)/creatinine(72)
(multiply by 0.85 for women)

Example: 70kg 75 year old man, Cr 1 mg/dl


Cr Clearance= (140-75)(70)/1.0(72)= 63
Example: 50 kg, 75 year old man, Cr 1 mg/dl
Cr Clearance= (140-75)(50)/1.0(72)= 45

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Example: Creatinine Clearance


vs. Age in a 55, 55 kg Woman
Age

Scr

CrCl

30

1.1

65

50

1.1

53

70

1.1

41

90

1.1

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Effects of Aging on Drug Excretion


Reduction in number of functioning
nephrons/decreased glomerular filtration
rate
Longer half-life of medications
Increased side effects
Increased potential for toxicity

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2. EFFECTS OF AGE ON
PHARMACODYNAMICS

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Pharmacodynamics
What the Drug Does to the Body
Generally, lower drug doses are
required to achieve the same effect with
advancing age.
Receptor numbers, affinity, or post-receptor
cellular effects may change.
Changes in homeostatic mechanisms can
increase or decrease drug sensitivity.
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Pharmacodynamics (PD)
Age-related changes:
sensitivity to sedation and psychomotor impairment
with benzodiazepines
level and duration of pain relief with narcotic agents
drowsiness and lateral sway with alcohol
HR response to beta-blockers
sensitivity to anti-cholinergic agents
cardiac sensitivity to digoxin

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
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PK and PD Summary
PK and PD changes generally result in
decreased clearance and increased
sensitivity to medications in older adults
Use of lower doses, longer intervals,
slower titration are helpful in decreasing
the risk of drug intolerance and toxicity
Careful monitoring is necessary to ensure
successful outcomes

3. ADVERSE DRUG EVENTS

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Adverse Drug Events (ADEs)


Responsible for 5-28% of acute geriatric
hospital admissions
Greater than 95% of ADEs in the elderly are
considered predictable
Approximately 50% are considered
preventable
Most errors occur at the ordering and
monitoring stages

Risk Factors for ADEs

Polypharmacy
Multiple co-morbid conditions
Prior adverse drug event
Low body weight or body mass index
Age > 85 years
Estimated CrCl <50 mL/min

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Most Common Medications


Associated with ADEs in the Elderly

Opioid analgesics
NSAIDs
Anticholinergics
Benzodiazepines
Also: cardiovascular agents, CNS agents,
and musculoskeletal agents

Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89.

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Adverse Drug Events


Some Adverse Drug Events 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.

Neuroleptic drugs may induce Tardive dyskinesia,


tremor, bradykinesia, rigidity
These may unmask underlying neurological disease
such as Parkinsons disease or be the total cause of the
presentation.
These range from antispychotic agents to
metoclopramide

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Other Risk Factors for Adverse Drug Events


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
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4. POLYPHARMACY

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Polypharmacy: The use of more


medication than is clinically
indicated or warranted.
Elderly population (> 65 yrs):
Constitute 13% of total population,
Purchase 33% of all prescription
drugs
Consume 40% of OTCs
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Polypharmacy leads to:


More adverse drug reactions
Drug-drug interaction
Decreased adherence to drug regimens
Poor quality of life
High rate of symptomatology
(Unnecessary) drug expense

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Risk rises exponentially as the number


of drugs increases
percent of patients with ADR

100

10

1
0

6
8
10 12 14
number of drugs taken

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18

20

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Drug reactions in the elderly often produce


effects that simulate the conventional image
of growing old:
unsteadiness
dizziness
confusion
nervousness
fatigue
insomnia

drowsiness
falls
depression
incontinence
malaise

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Avoid treating adverse reactions/side


effects of drug with more drugs!
Example:
Dizziness from anti-hypertensive treated
with meclizine
Edema from a calcium-channel blocker
treated with furosemide and KCL

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Drugs most frequently associated with


adverse reactions in the elderly:

psychotropic drugs-benzodiazepines
anti-hypertensive agents
diuretics
digoxin
NSAIDS
corticosteroids
warfarin
theophylline

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Polypharmacy and
Non-adherence
Non-adherence
Is a two-way street!
Physician factors
Patient factors

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Factors contributing to
Non-adherence
Large number of medications

Expensive medications

Complex or frequently changing schedule


Adverse reactions
Confusion about brand name/trade name
Difficult-to-open containers
Rectal, vaginal, SQ modes of administration
Limited patient understanding
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Optimal Pharmacotherapy
Balance between overprescribing and
underprescribing
Correct drug
Correct dose
Targets appropriate condition
Is appropriate for the patient
Avoid a pill for every ill
Always consider non-pharmacologic therapy
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Principles of Prescribing for Elderly


Uses the correct drug
Be as specific as possible and be cognoscente of
drug-drug and drug-disease interactions.

Prescribes the correct dosage


Start low and advance dosage slowly.
Use proper interval between dosing
Avoid drugs that affect multiple organ systems if
possible, be specific
Use drug that is appropriate for your patient
Failure in any one of these can result in adverse
drug events (ADEs)
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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!!!
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