1

Geriatric Pharmacology 

Nafrialdi

2

Why Geriatrics Pharmacology is Important

• Elderly population (> 65 yrs): • Constitute 13% of total population, • Purchase 33% of all prescription drugs • Consume 40% of OTCs• Thus, the elderly consume 3 times as much

drugs as the younger population• Elderly population is the fastest growing

population in the US

3

3

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

Why Geriatrics Pharmacology is Important

More new drugs are available each yearmost 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.

4

Changes in GeriatricsMultipathologiesReduced organ function Impaired homeostasisMultiple subjetive symptomps tendency of polipharmacy

5

Scope of Discussion

1. Effects of age on pharmacokinetics 2. Effects of age on pharmacodynamics 3. Polipharmacy4. Principles of prescribing for older

patients

6

1. EFFECTS OF AGE ON PHARMACOKINETICS

7

8

PHARMACOKINETICS • “What the Body Does to the Drug”

– Absorption– Distribution– Metabolism– Excretion

“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

9

Absorption

10

• 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

Influence of Age on Absorption

11

Influence of pH on drug absorption:

12

• 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.

Fick’s LawPassive diffusion occur only for most unionized form (usually lipid soluble), not for the ionized form (non lipid soluble)

Other Factors that Affect AbsorptionWhat 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.).

13

Overall: Amount of absorption (bioavailability) is usually not dramatically changed in most patients as a result of aging

Exceptionsdrugs with extensive first-pass metabolism,

bioavailability may increase (theophylline, digoxin, warfarin, b-blockers, Ca-antagonists, etc).

14

DISTRIBUTIONDistribution of drugs is much depends on body compositionChange of body composition change in Volume Distribution (Vd)

Young Adults Geriatrics

Body water 61% 53%

Lean body mass 19% 12%

Body fat 26-33 (women); 18-20 (men)

38-45 (women); 36-38 (men)

Serum albumin 4.7 g/dL 3.8 g/dL

15

16

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)

Decreased serum albumin • Increased free drug inceased effects/toxicity

17

Plasma Proteins

• In the blood: drug + protein forms drug-protein complex and circulate throughout the body

• Drug-protein complex dissociate very rapidly (reversible binding) (t½ ~ 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

Effects of Aging on Plasma Proteins

Influence of low albumin state may be significant if:Severe hypoalbuminemiaDrugs 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.

18

19

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

20

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 hemorrhageTolbutamide (displaced drug): protein binding 96%, Vd 0.12 l/kg

Phenylbutazone will displace tolbutamide from albumin free tolbutamide hypoglycemia

21

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

22

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

23

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

29

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

30

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)

Effect of Age on Drug EliminationMost 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 functionLeads to drug accumulation and toxicity if not

monitored, especially for drugs that are excreted in active

form such as digoxin, lithium, aminoglycosides, vancomycin etc.

31

Effects of Aging on Kidney Function

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

32

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)

33

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/dlCr Clearance= (140-75)(70)/1.0(72)= 63

Example: “50 kg”, 75 year old man, Cr 1 mg/dlCr Clearance= (140-75)(50)/1.0(72)= 45

34

Example: Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman

301.190

411.170

531.150

651.130

CrClScrAge

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

36

2. EFFECTS OF AGE ON PHARMACODYNAMICS

37

38

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.

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 antihypertensivesMultipathology 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

40

4. POLYPHARMACY

41

Polypharmacy leads to:More adverse drug reactions Drug-drug interactionDecreased adherence to drug regimensPoor quality of lifeHigh rate of symptomatology (Unnecessary) drug expense

42

Risk rises exponentially as the number of drugs increases

1

10

100

0 2 4 6 8 10 12 14 16 18 20number of drugs taken

perc

ent o

f pat

ient

s with

AD

R

43

44

• Drug reactions in the elderly often produce effects that simulate the conventional image of growing old:

unsteadiness drowsiness dizziness falls confusion depression nervousness incontinence fatigue malaise insomnia

45

• Drugs most frequently associated with adverse reactions in the elderly:– psychotropic drugs-benzodiazepines – anti-hypertensive agents– diuretics– digoxin – NSAIDS– corticosteroids – warfarin– theophylline

46

• Avoid routine treatment of adverse reactions/side effects of drug with other drugs!

Example:– Routine concomitant analgesic for treating

dizziness from anti-hypertensive drugs– Routin diuretic for Edema from a calcium-channel

blocker– Routine Potassium supplementation in patients

receiving diuretics

47

Principles of Prescribing for Elderly

• 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

48

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)

49

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!!!

50