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. 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 3

4. 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.

5. Changes in Geriatrics Multipathologies Reduced organ function
Impaired homeostasis
Multiple subjetive symptomps
 tendency of polipharmacy

6. Scope of Discussion Effects of age on pharmacokinetics
Effects of age on pharmacodynamics
Polipharmacy
Principles of prescribing for older patients

7. 1. EFFECTS OF AGE ON PHARMACOKINETICS

8. PHARMACOKINETICS
“What the Body Does to the Drug”
Absorption
Distribution
Metabolism
Excretion

9. Absorption
“Movement of drug from the site of administration into the blood stream”
How does absorption occur ?
Passive diffusion:
Absorption method for most drugs
Energy independent
Following concentration gradient
Active transport
Energy dependent
May opposite concentration gradient
Facilitated diffusion

10. Influence of Age on Absorption
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

11. Influence of pH on drug absorption:

12. Most drugs are weak electrolytes (weak acids or weak bases)
Fick’s Law
Passive diffusion occur only for most unionized form (usually lipid soluble), not for the ionized form (non lipid soluble)
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.

13. Other Factors 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.).

14. 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, warfarin, b-blockers, Ca-antagonists, etc).

15. 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
26-33 (women); (men)
38-45 (women); (men)
Serum albumin
4.7 g/dL
3.8 g/dL

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

18. 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.

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  hemorrhage
Tolbutamide (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

24. CYP3A4 : substrates • lidocaine • erythromycin • lovastatin
quinidine clarithromycin simvastatin
amiodarone • cortisol • diltiazem dexamethasone • ritonavir
Ca-antagonists • estradiol indinavir
nitrates tamoxifen
• carbamazepine • cyclosporin
• alprazolam • terfenadine
midazolam astemizole
triazolam • cisapride

25. CYP3A4 : inhibitors & inducers
• ketoconazole • ritonavir • phenobarbital
itraconazole indinavir phenytoin
• erythromycin • grapefruit carbamazepine
clarithromycin cimetidine • rifampicin
• nefazodone • dexamethasone
fluvoxamine • St. John’s wort
fluoxetine
• diltiazem
verapamil

26. CYP2D6 Substrates Inhibitors • amitriptyline • codeine • quinidine
imipramine dextromethorphan • paroxetine
clomipramine tramadol fluoxetine
• fluoxetine • metoprolol moclobemide
paroxetine propranolol • haloperidol
fluvoxamine timolol perphenazine
• haloperidol thioridazone
perphenazine
thioridazine (relatively resistant to induction)

27. CYP2C9 Substrates Inhibitors Inducers
• warfarin • fluvoxamine • rifampicin
• phenytoin fluoxetine • barbiturates
• tolbutamide • sulfaphenazole carbamazepine
glipizide • phenylbutazone
• losartan • fluvastatin
irbesartan • fluconazole
• diclofenac
ibuprofen
piroxicam
• fluvastatin

28. CYP2C19 Substrates Inhibitors Inducers
• S-mephenytoin • fluvoxamine • rifampicin
• omeprazole fluoxetine • carbamazepine
lansoprazole • omeprazole
pantoprazole lansoprazole
• proguanil • ketoconazole
• phenobarbital
• moclobemide

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)

31. Effect of Age on Drug 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.

32. Effects of Aging on Kidney Function
 kidney size
 renal blood flow
 number of functioning nephrons
 renal tubular secretion
Results: Lower glomerular filtration rate

33. 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)

34. Cr clearance=(140-age)(IBW)/creatinine(72)
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

35. Example: Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman30
1.1 90 41 70 53 50 65
CrCl
Scr
Age

36. 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

37. 2. EFFECTS OF AGE ON PHARMACODYNAMICS

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.

39. 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

40. 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

41. 4. POLYPHARMACY

42. 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

43. Risk rises exponentially as the number of drugs increases

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. Thank You