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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 Thus, the elderly consume 3 times as much drugs as the younger population
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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
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
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.
Changes in Geriatrics • Multipathologies • Reduced organ function • Impaired homeostasis • Multiple subjetivesymptomps tendency of polipharmacy
Scope of Discussion • Effects of age on pharmacokinetics • Effects of age on pharmacodynamics • Polipharmacy • Principles of prescribing for older patients
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 ? • Passive diffusion: • Absorption method for most drugs • Energy independent • Following concentration gradient • Active transport • Energy dependent • May opposite concentration gradient • Facilitated diffusion
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
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.
Other Factors that Affect Absorption • What is taken with the drug • Divalent cations (calcium, magnesium, iron) can affect absorption of manyfluoroquinolones (e.g., ciprofloxacin) • Enteral feedings interfere with absorption of some drugs • Drugs that affect GI motility can affect absorption (hyoscamine, dicyclomine, metoclopramide, cisapride, etc.).
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).
DISTRIBUTION • Distribution of drugs is much depends on body composition • Change of body composition change in Volume Distribution (Vd)
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
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 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.
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
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
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
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
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 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.
Effects of Aging on Kidney Function • kidney size • renal blood flow • number of functioning nephrons • renal tubular secretion • Results: Lower glomerular filtration rate
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)
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
Age Scr CrCl 30 1.1 65 50 1.1 53 70 1.1 41 90 1.1 30 Example: Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman
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
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 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
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
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
Drugs most frequently associated with adverse reactions in the elderly: • psychotropic drugs-benzodiazepines • anti-hypertensive agents • diuretics • digoxin • NSAIDS • corticosteroids • warfarin • theophylline
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
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
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)
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!!!