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Problems with Polypharmacy. Donald R. Noll DO FACOI Edited by Edward Warren, MD, Chair Geriatrics Carolinas Campus, March 2012 . D efine polypharmacy and recognize its associated problems. Apply principles of medication use and drug interactions to manage polypharmacy.
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Problems with Polypharmacy Donald R. Noll DO FACOI Edited by Edward Warren, MD, Chair Geriatrics Carolinas Campus, March 2012
Define polypharmacy and recognize its associated problems. Apply principles of medication use and drug interactions to manage polypharmacy. Discussthe hazards and specifics of herbal agents. Identify the difference between pharmacokinetic and pharmacodynamic drug interactions. Apply knowledge of the Cytochrome P450 enzyme system to prescribing and avoiding adverse interactions. List specifics about selected medications, their interactions, and adverse side effects. Learning Objectives
Use of greater than five medications is considered polypharmacy. The issue is the interaction, chemically and pharmacologically, between all of the medications a patient takes. It is a common problem in the elderly because they suffer from multiple chronic disease states You will have to deal with the problems of polypharmacy daily. Polypharmacy: A Serious Problem
In the US, the elderly are 12% of the population, but they take 25% of the prescription medications. Physicians prescribe most of these drugs, because patients expected us to solve their problems with a pill. Physicians are depended upon to advise wisely about medications. We must decide risks and benefits for each medication and re-assess at every clinical encounter. Polypharmacy
Say, “I believe in using as few medications as possible. We will prescribe only those medications you truly need.” The general public knows that too many medications are bad for them. The great majority of patients do not want to be on multiple medications. Its good to take the time to explain what each medication is for and be sure it is needed. How to be Popular…
They affect not only the targeted problem, but also other organ systems that also have responsive receptors. The more receptor specific a medication, the better it avoids adverse side effects. Examples: Verapamil -Ca channel blockade, constipation, edema, lower BP Oxybutynin – muscarinic acetylcholine blocker, urinary retention, dry mouth, constipation Drugs are blunt tools
Greater specificity, more focused drugs = Better Cox 2 inhibitor NSAIDS are more receptor specific. The GI system is less affected than with other NSAIDS, thus fewer GI bleeds. The risk is still not fully eliminated. Side effects often dose dependent Low doses are generally safer than high doses. Sometimes, two low dose drugs may be better than one high dose drug. This principle is commonly applied with anti-hypertensive medications. Two general principles
More aggressive treatment of Diabetes Mellitus, lipids and hypertension Multiple new drug treatments for dementia, CHF, and others New preventative treatments, like osteoporosis Growth of Alternative Therapies,nutraceuticals and herbal medications Why is polypharmacy growing?
Fragmentation of care managed care promoting compartmentalization multiple doctors, specialists, PA’s and NP’s prescribing Direct advertising by Drug companies Spending more on advertising than research! Literature and peer review encourages use of various drug therapies. Litigation worries Why is polypharmacy growing?
Physicians continue ill advised medications due to: Incomplete data base Multiple doctors involved Specialty intimidation Patient opinions Fear the patient may get worse Example: Study of stable CHF patients whose furosemide was discontinued 50% did fine 50% decompensated developing symptoms of pulmonary congestion from heart failure Why is polypharmacy growing?
Be Prepared and Skeptical • Know and apply the Beers’ List criteria. • Read “The Medical Letter” weekly. • Be skeptical about all medication claims.
Drug interactions The average elder takes 4.5 medications daily. The number of drugs is directly related to the risk of adverse drug related events. 15% risk of adverse events Two Drugs 50-60% risk of adverse events Five Drugs
After five medications, drug interactions rise sharply 10 drugs = about 4 interactions 12 drugs = about 10 interactions Individual medications vary Warfarin & amiodarone interact with many others. Gabapentin has few interactions. Fluoxetine (Prozac) blocks all of the hepatic enzymes (Cytochrome P450) other drugs need. Drug interactions
Two bad side effects can cancel each other out (Augmentin causes diarrhea) + (Hydrocodone causes constipation) = no bowel problem Two bad side effects can make matters worse (Verapamil causes constipation) + (Hydrocodone causes constipation) = very bad constipation Drug interactions
“Milton had an interesting side effect from taking St. John’s Wort.”
Little studied, little known Myth: Natural equals safety The more physiologic activity the more risk Herbal preparations, multiple substances means multiple actions, synergy. Example: GinkoBiloba antioxidant, inhibits platelet activating factor May interact with warfarin Drug interactions major area of future research Alternative Medications
Ginkgo Biloba • The active ingredients have antioxidant properties and inhibit platelet aggregation. It is said to improve cognitive function and blood flow. At least four reports of spontaneous bleeding in association with use of Ginkgo biloba have been published . • One described a 70-year-old man who presented with bleeding from the iris into the anterior chamber of the eye one week after putting himself on Ginkgo biloba concentrated extract (Ginkoba), 40 mg twice daily. He had a CABG performed 3 years previously and his only other medication was aspirin, 325 mg per day. After the spontaneous bleeding episode, he continued to take aspirin but discontinued the ginkgo product. Over a three-month follow-up period, he had no further bleeding episodes. Interaction of the ginkgo product and aspirin was considered the cause of his ocular hemorrhage.
Ginkgo Biloba • Ginkgo biloba can interact with warfarin (Coumadin). A 78 year old woman, who took warfarin for 5 years after a CABG, had a hemorrhagic stroke after using a ginkgo product for two months. It did not affect the PT/INR. The bleeding was attributed to the antiplatelet effects of ginkgo. • In another reported case, a 33-year-old woman had bilateral subdural hematomata after 2 years of ingesting Ginkgo biloba 60 mg twice daily. She also took acetaminophen and an ergotamine-caffeine preparation. While she was taking Ginkgo biloba, her bleeding times were prolonged. Within 35 days after she stopped taking the ginkgo product, her bleeding times were normal.
Ginkgo Biloba • Patients who take garlic, vitamin E, warfarin, aspirin, or other drugs with antiplatelet or anticoagulant effects should avoid ginkgo products. • Patients who are taking ginkgo products should be counseled to inform their physician about unusual bleeding or bruising, new-onset headaches or vision changes.
St. John's Wort • St. John's wort(Hypericumperforatum) is an herb widely promoted as a "natural" antidepressant. In Germany, it is commonly prescribed for various psychopathologic conditions involving depression and anxiety. • The safety and efficacy of St. John's wort are not evaluated in the appropriately designed studies that the FDA requires for antidepressant drugs.
St. John's Wort • The German monograph for St. John's Wort lists hypericin, a purported monoamine oxidase (MAO) inhibitor, as the active ingredient in the herb. • No instances of an interaction between tyramine-containing foods and St. John's Wort have been reported, but drug interactions may be of concern. • One report described a 50-year-old woman who had taken St. John's wort powder, in a dosage of 600 mg per day for 10 days, and then took one 20-mg dose of paroxetine (Paxil). She became incoherent and lethargic and also complained of nausea, weakness and fatigue.
St. John's Wort • Studies have shown that St. John's wort extract inhibits serotonin, dopamine and norepinephrine reuptake in vitro. • It would be prudent to avoid the concomitant use of St. John's wort and antidepressants until further information is available. • Given that the half-life of hypericin is 24 to 48 hours, a conservative recommendation would be to wait until two weeks after a patient has stopped taking St. John's Wort and then prescribe an antidepressant.
St. John's Wort • Side effects of St. John's wort include dry mouth, dizziness and confusion. • Phototoxicity manifested as elevated, itching, erythematous lesions has also been reported in association with the use of St. John's wort. • Neuropathy associated with sun exposure is another manifestation of phototoxicity. • In one case report, a 35-year-old woman developed stinging pain on sun-exposed areas after four weeks of self-treatment with ground St. John's wort. Her pain was worsened by cold, minimal mechanical stimuli and sun exposure. After she stopped taking St. John's wort, her symptoms resolved gradually over two months. The patient's symptoms were attributed to demyelination of cutaneous axons caused by photoactivatedhypericins.
Ginseng • Little scientific evidence shows that ginseng is effective for any purpose. • Nonetheless, this herb has been purported to strengthen normal body functions, increase resistance to stress and improve sexual function
Ginseng • Ginseng is generally well tolerated, but a probable interaction between it and warfarin has been reported. • A 47-year-old man with a mechanical heart valve who was taking warfarin to prevent thromboembolic events experienced a decline in INR from 3.1 to 1.5 two weeks after he began taking ginseng (Ginsana) three times daily to improve his "energy level." For the nine months before he started taking the ginseng product, his INR had ranged from 3 to 4. The patient denied other changes in drug therapy or diet, and he stated that he was not taking dietary supplements other than the ginseng product.
Ginseng • Two weeks after he discontinued use of the ginseng product, his INR was 3.3. Because of the risks associated with a decreased INR, the patient was not rechallenged with ginseng. • It would be prudent to closely monitor patients on warfarin who begin taking dietary supplements that contain this herb. A possible mechanism for this interaction is not yet known.
Kava • Kava is an herbal sedative with purported antianxiety effect. • In one case series involving four patients, kava was associated with extrapyramidal effects at dosages of 100 to 450 mg per day. Symptoms occurred 90 minutes after one patient took a single 100-mg dose, four hours after one patient took a single 100-mg dose, four days after one patient began taking 150 mg three times daily, and 10 days after one patient began taking 150 mg twice daily. • The extrapyramidal side effects included oral and lingual dyskinesia, torticollis, painful twisting movements of the trunk, oculogyric crisis and exacerbation of Parkinson's.
Kava • Two recent cases associated with kava: • 70-year-old man who had been taking kava extract for anxiety for two weeks experienced itching several hours after sun exposure. Erythematous, infiltrated plaques then developed on his face, chest and back. • A 52-year-old woman who presented with papules and plaques on her face, arms, back and chest after taking a kava extract. • In both cases, biopsy revealed lymphocytic infiltration of the dermis with destruction of the sebaceous glands. Because kava is lipophilic, it was hypothesized that kava can concentrate in sebaceous oils and trigger an immune response, resulting in a drug reaction.
One drug alters the concentration of another drug by changing the pharmacokinetics (metabolism) of that drug Pharmacokinetic
Digoxin concentration increases with quinidine or amiodarone. Rifampin increases clearance of phenytoin through Cytochrome P450 enzyme induction. Alcohol binge drinking decreases the metabolism of narcotics, benzodiazepines and warfarin. Coumadin + Paxil (Paraxetine) = elevated INR Pharmacokinetic Examples
Cytochrome P450 Enzymes • Most important: 1A2, 2C9, 2C19, 2D6, & 3A4. • Hepatic metabolism uses these to eliminate drugs and toxins from the body. • In some cases medications are activated y the action of these enzymes. • When this is the problem, it is a pharmacokinetic problem usually.
Alter the physiologic response to a second drug without altering the drug concentration Pharmacodynamic
Postural hypotension from multiple nitrates, calcium blockers, ace inhibitor and diuretics from alpha blocker for BPH + others from tricyclic antidepressants + others from calcium blocker + Digoxin + beta blocker + Amiodarone = bradycardia also Pharmacodynamic Examples
Ativan + haloperidol = sedation Alcohol + NSAIDS = GI Bleed Insulin + Beta Blocker = hypoglycemia with blunted clinical signs NSAID + ACE inhibitor = renal failure Warfarin + antibiotics = bleeding Pharmacodynamic Examples
When a drug induces or interacts with a disease process to cause an adverse event. Disease - Drug interactions
Plavix (clopidogrel) Tenormin (atenolol) Norvasc (amlodipine) Toradol (ketorolac) Prevacid (lansoprazole) Example: 80 y/o with Stroke, 2 MI’s, severe PVD, HTN, DJD and peptic ulcer disease, goes into acute renal failure after starting one of these drugs. The patient is on the following medications. A Disease – Drug Interaction The one most likely causing the renal failure is the Toradol(ketorolac). The patient has extensive atherosclerosis, including in the kidneys. The blood flow in the kidneys is thus more dependent upon the effect of prostaglandins. Taking this NSAID, antagonizes prostaglandins, causing a significant drop in blood flow to the kidneys. That would be less likely in a normal, disease free kidney.
Warfarin • Because of new clinical recommendations, the use of warfarin (Coumadin) has increased in recent years. • Almost all antibiotics can potentiate the effects of warfarin by inhibiting intestinal flora that produce vitamin K. • In addition, inhibition of the hepatic metabolism of warfarin occurs with ciprofloxacin (Cipro), clarithromycin (Biaxin), erythromycin, metronidazole (Flagyl) and trimethoprim-sulfamethoxazole (Bactrim, Septra). They inhibit critical Cytochrome P450 enzymes.
Warfarin • One case-control study showed acetaminophen causes of 30% of INR values greater than 6.0 in patients taking warfarin. • The mechanism is not known. • If APAP therapy is needed, the dosage should be as low as necessary. In addition, the INR should be monitored and the warfarin can be titrated in the context of the APAP. • Co-administration of acetylsalicylic acid (aspirin) and warfarin also increases the risk of bleeding, although the benefits of this combination may outweigh the risks in patients at high risk for arterial thrombosis. • This would be a pharmacodynamic drug interaction.
Warfarin • Administration of nonsteroidalanti-inflammatory drugs (NSAIDs) and warfarin increases the risk of bleeding. • The mechanisms of this interaction are antiplatelet effect and gastric mucosal damage. • This would be a pharmacodynamic drug interaction • Preliminary data suggest that the cyclooxygenase-2 inhibitor celecoxib (Celebrex) may be a safer option in patients requiring an NSAID and warfarin.
