Professional Documents
Culture Documents
Nafrialdi
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:
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)
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
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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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%
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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FD
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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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
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
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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PHASE II : conjugation
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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Serum creatinin may appear normal even when significant renal impairment exists.
Cr clearance=(140-age)(IBW)/creatinine(72)
(multiply by 0.85 for women)
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Scr
CrCl
30
1.1
65
50
1.1
53
70
1.1
41
90
1.1
30
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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
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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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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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Economic factors
May have to choose between food and medications
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4. POLYPHARMACY
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55
100
10
1
0
6
8
10 12 14
number of drugs taken
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20
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drowsiness
falls
depression
incontinence
malaise
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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
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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