The Stanford Health Library (healthlibrary.stanford.edu) regularly hosts community lectures. Many are recorded and posted to their video library. Here’s a lecture from 2013 featuring Mehrad Ayati, MD, a fantastic geriatrician at Stanford. The topic is polypharmacy — which means “multiple medications” — and the elderly. Dr. Ayati’s point is that there can be complications in taking multiple medications crucial to one’s health at any edge, but especially for seniors.
Dr. Ayati’s 80-minute lecture was recorded and can be found on youtube here:
Prescribing Drugs for an Aging Population: Polypharmacy and the Health of the Elderly
Webinar hosted by: Stanford Health Library
Speaker: Mehrdad Ayati, MD, geriatrician, Stanford
June 28, 2013
youtu.be/V8GImgKm4_M
Brain Support Network volunteer Denise Dagan listened to the recording and took extensive notes. She encourages everyone to listen to the lecture for themselves!
Her main take-aways from the lecture are:
* We expect oral medications to work for us because the pharmaceutical companies tell us they will, but it’s more complicated than that. It actually has a lot to do with your genetics, age, other medications (including over-the-counter medications and supplements), and even what you’ve just eaten when you swallow it. Any of those things can change the effectiveness of a drug, making it useless or toxic, resulting in side effects.
* Adverse drug reactions (ADR) account for 5-28% of acute hospital admissions. That’s 26 of every 1000 hospital beds, and 50 of every 1000 clinic visits. His example is a person in the hospital with a broken hip who fainted and fell in the bathroom due to a new medication.
* Dr. Ayati recommends patients become engaged with their doctor and pharmacist about their medications because he believes 51% of adverse drug effects are preventable. Specific actions you can take are at the end of his talk. They include:
Ask your doctor:
– Is this medication necessary?
– What is the therapeutic endpoint? How can I assess that? What is the target? What is it going to change?
– Does the benefit outweigh the risk?
– Is there a one medication I can use to treat two conditions at the same time?
– What is the potential drug-drug interaction?
– Can we use a simpler frequency? Rather than six times daily, twice or once daily?
Denise’s full notes are copied below.
Robin
====================================
Prescribing Drugs for an Aging Population: Polypharmacy and the Health of the Elderly
Webinar hosted by: Stanford Health Library
Speaker: Mehrdad Ayati, MD, geriatrician, Stanford
June 28, 2013
The geriatric population is prescribed the highest proportion of medications in relation to their percentage of the U.S population-13% of current geriatric population purchase 33% of all prescription drugs and this number will increase to 50% by 2040.
Prevalence of both adverse drug reactions and treatment failures increase in the older patients. Adverse Drug Events (ADEs) are responsible for 5-28% of acute geriatric medical admissions. It has been estimated that for every one dollar we spend on medications at nursing home facilities, we spend $1.33 in health care resources for the treatment of drug related morbidity and mortality.
In this review we will talk about the drug mechanism, why some people are able to tolerate some medications and why some others not, what we can do to change the nature of practice of medicine in the future and how we can provide more safety for us when we age.
Pharmacotherapy of the elderly is very complex because of:
1) Age-related physiologic changes
2) Multiple comorbidities (diagnosed with diabetes or high blood pressure at age 40 will start to see complications at age 60)
3) Multiple medications (prescription, over-the-counter, and herbal)
4) Multiple providers (prescribers and pharmacies). People don’t stop one prescription when they start a new prescription with another doctor.
Prescription Cascade is very typical (80-90% of people in his practice)
Example: Tell your doctor you’re not sleeping well, so the Dr. prescribes a sleep medication.
Months later you tell your doctor you’re drowsy during the day, so the Dr. prescribes a stimulant.
Months later you tell your doctor your heart is racing, so Dr. prescribes a beta blocker.
Months later you tell your doctor you’re depressed, so Dr. prescribes an anti-depressant.
Drugs and the Elderly
Good or Bad??
Successful Pharmacotherapy?
Challenges:
1. Polypharmacy
2. Different Pharmacokinetics and Pharmacodynamics
3. Nonadherence
4. ADE/ADR (adverse drug effects/adverse drug reactions)
5. DDI (drug drug interaction)
6. Beliefs
Frequency of ADE/ADR incidents:
5-28% of acute hospital admissions, 26 of every 1000 hospital beds, and 50.1 of every 1000 clinic visits.
Example: Person in the hospital because of a broken hip. They fell in the bathroom when they fainted due to a new medication
In nursing homes, for every $1 spent on medications, $1.35 in health care resources is consumed in the treatment of drug-related morbidity and mortality. 51% of that is preventable.
What is the journey of medication in your body? Even over-the-counter (OTC) and vitamins.
Every medication takes two pathways:
1. Pharmacokinetics: drug handling by the body
You take the medication by mouth and it travels through the body via the esophagus, stomach, small intestine (absorption), liver (metabolization), blood stream (distribution to affected tissues), kidneys (elimination of inactive ingredients)
Absorption:
* More absorption occurs in the small intestine
* Absorption shows the least change with aging. It is the same at 18 or 80.
* However, medications reduce absorption due to changes in stomach PH, food interaction, drug-drug interaction, drug-disease interaction.
Metabolism:
* The liver is the most common site of drug metabolism. It converts medication to a useable form and sends to the right part of the body to be of use.
* Aging is associated with a reduction in first-pass metabolism. Some of the medication is always lost in the liver (bioavailability of the drug), and aging reduces circulation to the liver so further reduces total amount that reaches the effective destination. The quickest, most effective administration of medication is in an IV because it bypasses the liver. Other ways to bypass the liver and allow drugs to be absorbed directly into the systemic circulation are: suppositories, intramuscular, inhalation aerosol, and sublingual (under the tongue).
** Two pathways in the liver: Phase I for most medications & Phase II eliminates the waste
Phase I: most medications. The drug will convert to metabolites of the lesser, or equal, or greater pharmacological compound, depending on whether the medication needs to be activated or diluted in the liver for proper effectiveness in the body. This is done through the CYP enzyme (cytochrome P450), the major enzymes involved in drug metabolism, accounting for about 75% of the total metabolism. Enzymes produced from the cytochrome P450 genes are involved in the formation (synthesis) and breakdown (metabolism) of various molecules and chemicals within cells.
CYP enzyme
* Declines with aging incrementally
* CYP3A4 > 50%
* CYP2D6 > 25-30%
* Variations in CYP encoding genes. If your CYP450 genes produce enzymes that metabolizes a drug slowly, the drug stays active longer and less is needed to get the desired effect. If your CYP450 genes produce enzymes that metabolize a drug fast, it will need more because you will burn through it quickly.
* TFs and ADRs
Example: PM (poor metabolizer) -vs- EM (excessive metabolizer) based on genetic background & CYP system.
CPP206 variants:
Two people, both with leg pain and taking codeine. 1 pill every 6hrs, as needed. The poor metabolizer will take one but not need another for more than 6 hours. The rapid metabolizer will be wanting to take them every 2-4 hours and the doctor will suspect addiction when it is just a metabolic difference. Both people are at risk for ADE/ADR.
Doctors can’t know who is whom. If you are a poor metabolizer and you take the medication every 6 hours, not knowing it is still in your system, you may start having adverse drug effects. With codeine, you may become drowsy, lightheaded. At the 3rd dose, they may be so dizzy when they get up to use the toilet, they fall and break a hip.
Codeine changes to morphine in the liver. A poor metabolizer needs less, a rapid metabolizer needs more.
Nortriptyline needs to become inactive in the liver.
Whenever prescribing a new drug for an elderly patient, always check to see whether the drug inhibits or induces the CYP enzymes.
Example: You are taking Warfarin (blood thinner) and a doctor prescribes ciprofloxacin (antibiotic) for a urinary tract infection. These two have drug interaction because ciprofloxacin inhibits the same CYP that the Warfarin needs for metabolization. So the patient will end up with too much Warfarin in their system and will be at risk of bleeding.
Example: Antifungal and antibiotic, one that induces CYP and the other inhibits same CYP, they are in conflict & neither works.
* This is a major source of adverse drug interactions
* For example, if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels.
Drug-Drug Interaction (DDI)
* Is a pharmacological or clinical response to the administration of a drug combination that differs from that anticipated from the known effects of each of the agents given alone.
* The most common pharmacokinetic interactions involve the inhibition of the CYP450 metabolism.
* The risk of DDI increases with the number of medications used, occurring in 13% of patients taking 2 medications and 82% of patients who take >6 medications. (baby aspirin, fish oil, vitamins, CoQ10, blood pressure can all conflict in the liver)
Drug-Nutrient Interaction
* A Classic example is the reduction of iron absorption from food in the presence of antacid drugs, essentially because of a DDI.
Grapefruit !
* The concomitant administration of grapefruit juice can increase the plasma concentration of numerous drugs and decrease the concentration of others.
* Chemicals in the juice inhibit CYP3A4 drug-metabolizing enzyme in the small intestine, increasing the bioavailability and plasma concentration of drugs with a high first-pass metabolism (e.g., felodipine, amiodarone, cholesterol-lowering statins)
Over-the counter (OTC) medications
* Adds to the challenge of prescribing appropriate medications for older patients.
* It presents a further risk for ADRs and interactions because:
** People don’t tell their doctor(s) what they’re taking, especially vitamins (nutri-ceuticals!)
** People don’t recognize that they are pharmaceutical agents.
** As OTC medications grow rapidly, their use by older adults become more of a problem
** There are more than 100,000 OTC medications currently in the market – and growing! Doctors can’t possibly know the DDI.
1) Brand names vs generic names
2) Different packaging
3) Multiple ingredients
4) Small-font labels
5) Uncertain about purpose of medication
6) Lack of knowledge of the seller, Patient, and Physician
7) Risk of Prescription Cascade
Herbal Medications
* Are not regulated by the US Food and Drug Administration
* Difficult to predict the potential for interactions with prescription of OTC drugs
* Almost 1/3 of current users of herbal medicines are at risk for herb-drug interactions because they inhibit the CYP system.
* Systems such as the CYP450 are particularly vulnerable to modulation by the active constituents of herbs
* Many herbs have been identified as substrates, inhibitors, and/or inducers of various CYP enzymes, which may have important clinical and toxicological consequences. CoQ10, garlic, echinacea, ginkgo, ginseng, glucosamine, saw palmetto, st. john’s wort, valerian.
* As an example, many anti epileptic drugs are known to interact with herbals and botanicals, because all first generation entiepileptic drugs (e.g. carbamazepine, valproic acid, phenytoin, phenobarbital, primidone) are CYP inducers or inhibitors.
Personalized Medicine
A group of people with the same diagnosis and same prescription will break into four groups based on CYP genetics:
– toxic, but beneficial
– toxic but not beneficial
– not toxic and not beneficial
– not toxic and beneficial
Example: SSRI antidepressant medication. 40% of people don’t respond to this medication because of polymorphism in genes. Some will have side-effects.
Example: Proton pump inhibitors (Prilosec, Prevacid, Nexium) 21 clinically relevant polymorphisms. Actually works better in Asian population because of genetics, than in whites and blacks.
Example: Acetylcholinesterase inhibitors (Aricept, Exelon). Some people it doesn’t work at all.
Example: Warfarin study found adjusting the dose based on genetic background, people have a better result.
Example: Plavix box actually states some people, especially Asian, is nonfunctional and can have more cardiovascular problems and bleeding.
The future will include testing of CYP genetic background so doctors can use that information for prescriptions that work.
Distribution of Medication, or Vd
* Locations in the body a drug penetrates and the time required of the drug to reach such locations.
* It is expressed as the volume of distribution (Vd)
* Altered by age-associated changes in body composition.
With age, there is:
1) Decrease in lean body mass
2) Total body water
3) Increase in body fat.
Hydrophilic drugs like water (digoxin, ethanol, theophylline, lithium) >>>> lower Vd due to less body water and lean body mass.
Example: Digoxin toxicity develops over years because less water and muscle in older people, so people end up in the hospital if you don’t adjust the dose. Digoxin, distributes and binds to muscles, will reduce Vd due to reduced muscle mass.
Example: alcohol consumption is the same over the decades, but as water reduces in the body the effect of alcohol on the body will begin to cause hangovers. If you have 1-2 glasses of water with the wine, you will compensate and reduce chance of hangover.
Lipophilic drugs like fat (benzodiazepines, Ativan, Xanax, lidocaine) and have an increased Vd
* Take longer to reach steady-state concentration and longer to eliminate from the body when you have more body fat.
Two patients with the same genetic background, one 20-years-old, one 60-years-old, both given 1mg of Ativan, the 20-year-old will be fine, but the 60-year-old will be very drowsy.
* Another issue is binding:
A drug’s efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse.
Albumin protein binds to drugs and takes it to its effective destination in the body. Older people produce less albumin than younger people. Albumin levels may be decreased significantly in older adults with malnutrition or chronic diseases, resulting in an increase in the “free” active drug concentration to unacceptable levels despite “normal” total serum concentration. “Free” active drug causes side-effects and toxicity.
Competition:
* For example, assume that drug A and drug B are both protein-bound drugs
* If drug A is given, it will bind to the plasma proteins in the blood. If drug B is also given, it can displace drug A from the protein, thereby increasing drug A’s fraction unbound.
* This may increase the effects of drug A, since only the unbound fraction may exhibit activity.
Elimination:
* Drug’s final route of exit from the body
* For most drugs, this involves elimination by the kidney.
* The effects of aging on renal function have been studies extensively; it is well documented that renal function begins to decline when people reach their mid-30s and continues to decline an average of 6-12ml/minute/1.73 m2 per decade.
2. Pharmacodynamics: response to medication
Describes how drugs exert their effect at the site of action and the time course and intensity of pharmacological effect. You need a receptor in the destination organ. If all the receptors are taken by the drug that first arrives, the next drug taken has no receptors to be taken up and they become ‘free’ and cause side-effects.
What can we do??
* Optimizing drug therapy
* Make balance between under prescribing and over-prescribing of beneficial therapies
* Make principles for prescribing in health care providers
Principles for health care providers
* Start slow and low dose
* Titrate dose gradually as tolerated
* Not start two medications at the same time
Ask your doctor:
* Is this medication necessary?
* What is the therapeutic endpoint? How can I assess that? What is the target? What is it going to change?
For example: If you are taking antidepressant medication and you don’t notice a difference, when do you stop taking it?
* Does the benefit outweigh the risk?
* Is there a one medication I can use to treat two conditions at the same time?
* What is the potential DDI?
* Can we use a simpler frequency? Rather than six times daily, twice or once daily?
Your job before a doctor visit:
* Bring all bottles of medications include OTC and herbals to office at each visit
* Ask every time about ADE/ADR
* Bring list of bottle of medication prescribed by another doctor
* Ask your physician to write any change in frequency, dosage in writing and share with other caregivers
* Make a good relationship with your doctor
Don’t forget!
* Discontinuing specific medications in certain patient populations does not worsen outcomes, decreases risk of ADRs, and reduces cost of medications.
* Always need to check with your physician to discontinue a medication to avoid ADR-withdrawal symptoms.
Q&A
How do you know if your medication is inhibiting or inducing in your liver with the CYP enzymes?
It’s on the insert the pharmacist gives you with your prescription. You can have a consult with your pharmacist about drug interaction potential if you get all your prescriptions filled at the same pharmacy. Sometimes pharmacists will call doctors and question their prescription due to drug interaction.
Grapefruit-drug interaction?
The pharmacy insert will say not to take certain medications with the grapefruit at the same time. If your medication is inhibited by grapefruit and you always have grapefruit with breakfast, you can take your medication with lunch. As long as there is some time between, you should be fine.
Current state of personalized CYP mapping?
There are some companies doing it, but it is not covered by insurance. Its just a sample from inside your cheek.
Congress has a 2009 act that nobody can use genetic info against you, including insurance companies to raise your rates.
If you kept good records of your interactions of drugs, can you ascertain from that which CYP system your genetics are?
Sure, but it wouldn’t be easy. You would need to have the doctor and pharmacist on board to document everything.
Takes Gabapentin and pain medication. Pharmacy insert says the pain medication will reduce the effect of gabapentin.
That’s exactly what the lecture was talking about.
Will gabapentin or lyrica cause your blood to become thinner?
Yes, those and others reduce platelet count, which also increases your risk of bleeding.
Pharmacist working on Aleve experienced the phenomenon of this talk with animal testing before they understood the genetics of this. Dogs don’t have the CYP system to metabolize it.
What are the symptoms of a drug interaction, especially in seniors who don’t communicate well and/or this is all so new they wouldn’t know how to express the problem and that feeling unwell may be due to medications.
If the person is having mental or physical changes you can suspect a drug interaction. Even medications they have been taking for awhile can begin to cause problems because of the changes of aging. First thing needs to be a review of the medications list, including OTC and herbals.
For better pain control, Norco pain medications should increase the morphine part once the Tylenol part is maxed-out IF you can tolerate an increased morphine portion.
FDA reduced max dose of Tylenol from 4g to 3g in 2012 because of liver damage, especially because Tylenol is combined with so many cold/flu medications and morphine derivatives.