Dr.

DOHA RASHEEDY ALY

Lecturer of Geriatric Medicine Department of Geriatric and Gerontology Ain Shams University

Scope of the issue Pharmacokinetics Pharmacodynamics Adverse drug reactions and adherence Underuse of drugs Nonprescription and alternative therapies Common sense solutions

 Elderly account for 1/3 of prescription drug use, while only 13% of the population. One survey: Average of 5.7 prescription medicines per patient. Average nursing home patient on 7 medicines.

 Surveys indicate that elders take average of 2-4 nonprescription drugs daily. Laxatives used in about 1/3-1/2 of elders many who are not constipated. Non-steroidal anti-inflammatory medicines, sedating antihistamines, sedatives, and H2 blockers are all available without a prescription, and all may cause major side effects.

 Pharmacokinetic Pharmacodynami Changes cs Changes

ABSORPTION DISTRIBUTION ELIMINATION (METABOLISM
& EXCRETION)

There is little evidence of any major alteration in drug absorption with age. However, conditions associated with age may alter the rate at which some drugs are absorbed. Such conditions include:
greater consumption of nonprescription drugs (eg, antacids and laxatives) changes in gastric emptying, which is often slower in older persons, especially in older diabetics.

 Decrease in total body water (due to decrease in muscle mass) and increase in total body fat affects volume of distribution. Water soluble drugs: lithium, aminoglycosides, alcohol, digoxin
Serum levels may go up due to decreased volume of distribution

Fat soluble: diazepam, thiopental, trazadone

Half life increased with increase in body fat

 Albumin concentration: Drugs such as phenytoin, salicylates, and disopyramide are extensively bound to plasma albumin. Albumin levels are low in many disease states, resulting in lower total drug concentrations. 2. Alpha1-acid glycoprotein concentration: 1-Acid glycoprotein is an important binding protein with binding sites for drugs such as quinidine, lidocaine, and propranolol. It is increased in acute inflammatory disorders and causes major changes in total plasma concentration of these drugs even though drug elimination is unchanged.

 decrease in serum albumin(which binds many drugs, especially weak acids) There may be a concurrent increase in serum orosomucoid ( -acid glycoprotein), a protein that binds many basic drugs. Thus, the ratio of bound to free drug may be significantly altered.

 The capacity of the liver to metabolize drugs does not appear to decline consistently with age for all drugs. The greatest changes are in phase I reactions, ie, those carried out by microsomal P450 systems. There are much smaller changes in the ability of the liver to carry out conjugation (phase II) reactions
1. 2. Some of these changes may be caused by decreased liver blood, there is a decline with age of the liver's ability to recover from injury, eg, that caused by alcohol or viral hepatitis. Therefore, a history of recent liver disease in an older person should lead to caution in dosing with drugs that are cleared primarily by the liver, even after apparently complete recovery from the hepatic insult. Finally, malnutrition and diseases that affect hepatic functioneg, heart failureare more common in the elderly. Heart failure may dramatically alter the ability of the liver to metabolize drugs by reducing hepatic blood flow. Similarly, severe nutritional deficiencies, which occur more often in old age, may impair hepatic function.

3.

4.

 Variable changes in first pass metabolism due to variable decline in hepatic blood flow (elders may have less first pass effect than younger people, but extremely difficult to predict). Acetylation and conjugation do not change appreciably with age Oxidative metabolism through cytochrome P450 system does decrease with aging, resulting in a decresed clearance of drugs Hepatic blood flow extremely variable

 GFR generally declines with aging, but is extremely variable

30% have little change 30% have moderate decrease 30% have severe decrease

Serum creatinine is an unreliable marker. If accuracy needed, do Cr Cl. The Cockroft and Gault Equation
Cr Cl = 140-age(yrs) X wt (kg) X .85 for women Cr (mg/100ml)X72
May overestimate Cr Cl, especially in frail elders

 Some effects are increased

Alcohol causes increase is drowsiness and lateral sway in older people than younger people at same serum levels Fentanyl, diazepam, morphine, theophylline
Some effects are decreased

Diminished HR response to isoproterenol and beta -blockers

Unnecessary drug Not prescribing new needed Rx Contraindicated drug Dose too low or too high Adverse drug event/ drug interaction Nonadherence Prescribing cascade

 Recent studies reported that under-prescribing of medications for the elderly lead to negative health outcomes. Specifically, this refers to the use of b-blockers and thrombolytics in the treatment of a myocardial infarction (MI) and warfarin to prevent stroke in patients with atrial fibrillation
CAD Beta blockers only 21% of eligible patients received b-blocker therapy . Age greater than 75 years was associated with underuse of b-blockers. The mortality rate was 43% less among b-blocker recipients than non recipients. ASA Anticoagulation in AF:more than 20% of patients with risk factors for stroke and no contraindications to anticoagulation were not receiving antithrombotic therapy. Of this group, 34% were prescribed aspirin, even though they did not have contraindication to anticoagulation HTN, especially systolic HTN Pain
Particular fear of narcotics in the elderly

 A case control study has reported that the use of nonsteroidal antiinflammatory drugs (NSAIDs) is correlated with initiation of antihypertensive therapy in the elderly population. a recent clinical trial demonstrates that the addition of ibuprofen to antihypertensive therapy with hydrochlorothiazide reduced blood pressure control. The OTC use of NSAIDs has also been recognized as an important cause of upper GI hemorrhage . The use of these medications is frequently self-directed, and while they are generally very safe, patients may not recognize that ibuprofen, naproxen, and fenoprofen or famotidine, ranitidine, cimetidine, and nizatidine are from the same pharmacologic classes. Patients may use multiple products from within the same pharmacologic class unless they are specifically advised always to consult the pharmacist or physician.

 Natural products may have benefits, side effects, and drug interactions Very commonly used in the elderly Some common herbs and alternative therapies: Anti-aging DHEA, growth hormone Dementia Gingko biloba BPH Saw palmetto OA Chondroiton sulfate, glucosamine Depression St. Johns wort

 Ginkgo may increase anticoagulant effects of ASA, warfarin, NSAIAs, ticlopidine. Kava: is used to treat anxiety. It's also used to relieve insomnia and nervousness. Do not take Kava if you have a history of liver problems. Also do not mix with antidepressants, sedatives, and do not mix Kava with alcohol. Licorice: used to treat coughs, colds and peptic ulcers. High doses can lead to increased blood pressure, water retention and potassium loss. Do not use with diuretics or digoxin because it could lead to further loss of potassium, essential for heart function. St. John's wort: a natural anti-depressant for mild to moderate depression. Do not take with other anti-depressants, HIV medications, oral contraceptives, Tamoxifen (a cancer drug). Valerian: a mild sedative with hypnotic effects, used to promote sleep, Should not be taken with alcohol or Valium.

 About 15% of hospitalizations in the elderly are related to adverse drug reactions. The more medications a person is on, the higher the risk of drug-drug interactions or adverse drug reactions. The more medications a person is on, the higher the risk of non-adherence. Most clinical trials published today focus on adults less than 70 years old. As geriatric health care providers, we often put our patients at risk by trying medications that have shown benefit in younger patients in hopes of similar results in our older patients

 Many drugs commonly prescribed for older patients result in potentially life-threatening or disabling adverse reactions. Cardiovascular and psychotropic drugs are the agents most commonly associated with serious adverse reactions in the elderly.
This fact results from a combination of their narrow therapeutic-toxic window, age-related changes such as reduced renal excretion, and a prolonged duration of action, which predisposes the older patient to adverse reactions.

Adverse drug reactions are often not recognized because the symptoms are nonspecific or mimic the symptoms of other illnesses. Often another drug is prescribed to treat these symptoms, resulting in polypharmacy and further increasing the likelihood of an adverse drug reaction. An overstatement that is of great clinical use and forms a good starting point for clinical evaluation can be stated as follows: Any symptom in an elderly patient may be

a drug side effect until proved otherwise.

 Common cause of ADEs in elderly Almost countless good role for pharmacist and computer or on-line programs Some common examples Statins and erythromycin and other antibiotics TCAs and clonidine or type 1Anti-arrythmics Warfarin and multiple drugs ACE inhibitors increase hypoglycemic effect of sulfonylureas

 Patient with PD have increased risk of drug induced confusion. NSAID (and COX-2s) s can exacerbate CHF. Urinary retention in BPH patients on decongestants or anticholinergics. Constipation worsened by calcium, ahticholinergics, calcium channel blockers. Neuroleptics and quinolones lower seizure thresholds

1. Complete drug history, including herbs and nonprescription drugs 2. Avoid medications if benefit is marginal or if nonpharmacologic alternatives exist 3. Consider the cost 4. Start low, go slow, but get there! 5. Keep regimen as simple as possible 6. Write instructions out clearly 7. Have patient bring in medications at each visit. 8. Consider medication box or mediset 9. If things dont make sense, consider a home visit 10. Discontinue drugs when possible if benefit unclear or side effects could be due to drug 11. Be cautious with newer drugs

 Interactions between drugs and food

warfarin and Vitamin K containing foods (remember green tea, as well) Phenytoin & vitamin D metabolism Methotrexate and folate metabolism

Drug impact on appetite

Digoxin may cause anorexia ACE inhibitors may alter taste

 Try non-pharmacological approaches such as walking or regular activity or exercise, getting adequate sleep, quitting smoking, consuming alcohol in moderation and dietary changes toward a healthier lifestyle.

Drug 1
ADE interpreted as new medical condition

Drug 2
ADE interpreted as new medical condition

Drug 3
Rochon PA, Gurwitz JH. Optimizing drug treatment in elderly people: the prescribing cascase. BMJ 1997;315:1097.

 Common cause of polypharmacy in elderly Some common examples NSAID->HTN->antihypertensive therapy Metoclopromide ->Parkinsonism ->Sinemet Dihydropyridine -> edema ->furosemide NSAID ->H2 blocker ->delirium ->haldol HCTZ ->gout->NSAID ->2nd antihypertensive

Multiple chronic disorders Multiple prescribers Multiple prescriptions Multiple doses Change in daily drug regime Cognitive or physical impairment Living alone Recent Hospital discharge Inability to pay for drugs Presence of side effects

 1. Making drug regimens and instructions as simple as possible.

a. Use the same dosage schedule whenever feasible (e.g., once or twice per day) b. Time the doses in conjunction with a daily routine.

2. Instruct relatives and caregivers on the drug regimen. 3. Enlist others (e.g., home health aides, pharmacists) to help ensure compliance. 4. Make sure the older patient can get to a pharmacist (or vice versa), can afford the prescriptions, and can open the container. 5. Use aids (such as special pillboxes and drug calendars) whenever appropriate. 6. Keep updated medication records 7. Review knowledge of and compliance with drug regimens regularly.

 Is there a specific indication for the drug, and is it effective? Every drug should be matched to a welldocumented diagnosis. The use of drugs unpaired to a diagnosis should be carefully reevaluated and their use discontinued whenever possible.

Is the dosage appropriate, given renal and hepatic function? Are the instructions for use practical and appropriate to the person? In the hospital, complicated
dosing regimens for drugs such as warfarin permit the careful titration of therapy to the person. At home, dosing regimens should be as simple as possible. Whenever possible, doses should be linked to specific daily events such as bedtime to minimize problems.

- Definition: The process of comparing a patients medication orders to all medications that the patient has been taking.

Medication Reconciliation will avoid:

1. omissions, 2. duplications 3. dosaging errors 4. drug interactions

 Polypharmacy means "many drugs. The use of more medication than is clinically indicated or warranted.
5 or more drugs 7 or more drugs

 The elderly use more drugs because illness is more common in older persons.
Cardiovascular disease Arthritis Gastrointestinal disorders Bladder dysfunction

 Polypharmacy leads to:

More adverse drug reactions Decreased adherence to drug regimens
Patient outcomes Poor quality of life High rate of symptomatology (Unnecessary) drug expense

 The most consistent risk factor for adverse drug reactions is:
number of drugs being taken
Risk rises exponentially as the number of drugs increases.

 Annual Brown Bag

At least yearly, and more often if indicated, ask elderly patients to bring in all medications they have at home.
Prescription Over-the-counter Vitamins supplements Herbal preparations

 I dont knowthe doctor told me to

Digoxin Allopurinol Antidepressants Anticonvulsants Anxiolytics

Discontinuing unnecessary medications is one of the most important aspects of decreasing polypharmacy Drugs without indications should be stopped!

 Acetaminophen as effective as NSAIDs in mild OA NSAIDs side effects

GI hemorrhage (less with COX-2) Decline in GFR (COX-2 as well)

Can Worsen BP- removal of NSAID can affect mean blood pressure control Fluid retention, Worsen CHF

Decreased effectiveness of diuretics, antihypertensive agents Indication should justify the increased toxicity of NSAIDs Newer Cox-2 agents, gastric sparring Less risk of Alzheimer's and cognitive decline

 Phenothiazine major tranquilizers (promethazine, thorazine, chlorpromazine, haloperidol) Tricyclic anti-depressants (imipramine, amitriptyline, nortriptyline, desipramine) Narcotics-demerol, codeine, morphine Anti-spasmotics-oxybutynin, diclomine, tolterodine, probanthine, atropine, hyoscyamine, probanthine, belladonna alkaloids. Anti-histamines : Diphenhydramine, Cyproheptadine, OTC cold medications, OTC sleep agents, Trihexyphenidyl, Benztropine

 B-Blockers (propranolol)-side effects of:

Precipitation of or exacerbation of CHF Masking of hypoglycemia Development of hypotension Masking of symptoms of endocrine disease (hypothyroidism) Exacerbation of chronic lung disease or bronchospasm Depression Memory loss

use selective ones: atenolol and metoprolol

Less side-effect profile Better compliance-once or twice daily Use associated with reduced cardiovascular morbidity and mortality in high risk patients

 Alpha-methyl-dopa Clonidine Alpha-blocking agents: useful for combined hypertension and prostatic hyperplasia Reserpine

 Once daily dosing increases compliance Inexpensive First line agents effective in reducing risk of stroke and CV disease Thiazides generally not effective in the presence of renal insufficiency, May cause hypercalcemia Contribute to or cause incontinence Adverse reactions
Dehydration; postural hypotension; K loss (especially during the summer and sweating)

Consider discontinuing in elderly when possible, especially advanced, demented, or depressed elderly (reduced thirst and appetite drive)

Worsen dementia and delirium Cause hip fractures and falls Cause postural hypotension Risk of tardive dyskinesia with phenothiazines

 Cause Hypoglycemia-- chlorpropamide SIADH more frequent with aging (idiopathic 30%)

(Few indications currently for use except for rate control or congestive heart failure to improve function). Side-effects:
Confusion Anorexia Nausea Yellow Green Colors Agitation Depression

 May cause cognitive dysfunction Have anti-cholinergic side effects urinary retention constipation dry mouth sedation

Anorexia Nausea Arrhythmias Hypotension Drug-drug interactions-erythromycin, cimetidine, diazepam, phenytoin Useful for acute wheezing or asthma, not for COPD

 Anticholinergic Sedation Cognitive dysfunction Dry mouth Blurred vision Constipation Urinary retention

Sedation Falls Anti-cholinergic side-effects Contraindicated in elderly

 Beta blocker preparations-can achieve significant systemic absorption leading to heart block, CHF, bronchospasm.

 Common cause of potentially reversible cognitive impairment Demented patients are particularly prone to delirium from drugs Anticholinergic drugs are common offenders (TCAs, benadryl and other antihistamines, many others) Other offenders cimetidine, steroids, NSAID

 Biggest risk drugs are long acting benzodiazepines and other sedative-hypnotics Both SSRIs and TCAs associated with increased risk of falling Beta blockers NOT associated with increased risk of falling in published literature Mild increase in fall risk from diuretics, type 1A anti-arrythmics, and digoxin

 Reduced thirst and appetite with normal aging Reduced thirst and appetite is associated with depression and/or dementia DRUG induced ANOREXIA:
Theophylline Macrodantin Pronestyl Digoxin Thyroxin SSRIs

 Liver- cirrhosis, malnutrition, malignancy, hepatitis with resultant decreased albumin and total protein levels (ex: sodium warfarin and phenytoin Kidney- chronic renal insufficiency, renal failure Brain-dementia, delirium Intestinal tract- malabsorption syndrome stomach- gastritis

 Narcotics Begin lactulose or sorbitol and a stimulant laxative Steroids Think about osteoporosis prevention Remember steroid induced diabetes

 Meperidine Diphenhydramine The most anticholinergic tricyclics: amitryptiline, doxepin, imipramine Long acting benzodiazepines such as diazepam Long acting NSAIAs such as piroxicam High dose thiazides (>25mg) Iron: 325 mg once daily is enough.

 First article published August 2009

Consult Pharm 2009;24:601-10. http://www.ascp.com/resources/clinical/upload/BeersCri teria.pdf

Focus on CNS medications Consensus panel of geriatricians, other providers

 Mr. W. is a 86 year old man with pulmonary HTN, COPD, CRI (creatinine of 2.2), CHF with an ejection fraction of 20%, mild dementia, depression, and severe anemia. He is frequently admitted to the hospital because of severe disease and poor adherence with his medical regimen. His discharge medications on last admission one month ago were aspirin 325mg, 02, enalapril 20mg QD, furosemide 80mg BID, combivent, and sertraline 50mg. The inpatient team decided that he was undertreated, and added metoprolol 12.5mg BID, aldactone, FeSo4 325mg TID, and 3 inhalers. He was readmitted within a week. How might you approach his regimen?

 This man has already shown that he is not adherent, and adding medications to his regimen has probably made his adherence worse. Asking him about adherence can be revealing. In this case, he admits that he is just taking too many medications and so randomly stopped a few. He also is complaining about urinating all day, so almost always skips his PM furosemide.

Although beta blockers improve outcomes in severe CHF, in this man is who marginal with his medications, had lung disease, and limited insight, it may not be worth it. Keeping the regimen simple is more likely to result in success. Likewise, his iron, if he needs it at all, would be adequate at a once daily dose. Probably combivent would be a better choice to improve adherence.
RCTs have demonstrated decreased mortality with both beta blockers and aldactone in CHF. However, applying those results to this man with multiple severe diseases, mild dementia and decreased adherence may not be wise. So, in short we recommend: Changing furosemide to 120mg once daily D/c feSo4 or decrease it to once daily Drop metoprolol and aldactone Change inhaler back to combivent

Mrs. F. is a 92 year old nursing home resident with a history of HTN, heart disease, osteoarthritis, and a stroke. She has been declining recently, with a decreased appetite. Her meds are HCTZ 12.5, ASA 81, digoxin .125, and enalapril 10. She has been on the same meds and dosages for years. On exam, she looks frail BP 130/80 P60 R 16. Other than being thin, her exam is fairly unremarkable. She has no signs of CHF. She has mild left sided weakness and hyperreflexia, and her MMSE is 27/30, she is not depressed. Her gait is slow with a walker. Labs: Hgb12, Cr 1.3, BUN 20, digoxin level 1.7, others normal. Her EKG is normal except for borderline bradycardia and nonspecific ST changes, which are old.
What do you think is wrong?

 Digoxin can cause toxicity even with normal serum levels. When you stopped her digoxin, her appetite went back to normal. It is not uncommon for nursing home patients may be on digoxin for unclear indications.

An 83 y/o woman is brought to the ER because of dizziness on standing, followed by brief LOC; the patient now feels well She has hypertension but is otherwise healthy Daily medications: metoprolol 50mg/d, captopril 25 mg/d, and nitroglycerin 0.4mg SL prn BP is 130/70 mmHg sitting and 100/60 standing; PE is otherwise normal; CBC, BUN, ECG, CMP are all normal

Which of the following is the most likely cause of this syncopal episode? Sepsis Drug-related event Hypovolemic hypotensive episode Cardiogenic shock Unidentifiable cause

80 yr. widow who now lives with her daughter comes to your office to establish care and complains of being a nervous wreck and not being able to turn off her mind for the past 2 yrs. She brings with her a bag of all her meds. PMHx: CHF, irritable bowel syndrome, depression, HTN, recurrent UTIs, stress incontinence, anemia, occipital headaches, osteoarthritis, generalized weakness Meds: sucralfate 1gm TID, cimetidine 300mg QID, enteric asa 325mg, atenolol 100mg, digoxin 0.25, alprazolam 0.5mg, naproxen 500mg TID, oxybutynin 5mg BID, dicyclomine 10mg TID, lasix 40mg , Tylenol #2 prn

 High risk drugs: alprazolam, oxybutynin, tylenol #2 (narcotics), dicyclomine, NSAIDS Digoxin at a higher then recommended dose (0.125mg) naproxen and aspirin carry the potential drug related adverse events of gastritis/GIB and sucralfate and cimetidine are being used to treat these side effects

 The elderly take more medications than any other age group Pharmacokinetics and pharmacodynamics are altered Adverse drug reactions are common Risks go up with the number of drugs used Nonprescription and herbal therapies are common With care and common sense, we can probably do a better job