March 2017 - Page 5 of 8 - Brain Support Network

“Jumping Genes Suspected in Alzheimer’s” – mitochondria cascade hypothesis

Date March 9, 2017

“Jumping Genes Suspected in Alzheimer’s” – mitochondria cascade hypothesis

This article from Duke Today (today.duke.edu) describes the “Alu neurodegeneration hypothesis,” also known as the “mitochondrial cascade hypothesis.”

Here’s an excerpt:

“The dominant idea guiding Alzheimer’s research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause. The Duke study builds on an alternative hypothesis. First proposed in 2004, the ‘mitochondrial cascade hypothesis’ posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die.”

The full article is below.

Robin

———————-

today.duke.edu/2017/03/jumping-genes-suspected-alzheimers

Jumping Genes Suspected in Alzheimer’s
Mechanism might explain initial stages of neurodegenerative disease
Duke Today|Research
By Robin A. Smith, Duke Research
Published March 8, 2017

DURHAM, N.C. — The latest round of failed drug trials for Alzheimer’s has researchers questioning the reigning approach to battling the disease, which focuses on preventing a sticky protein called amyloid from building up in the brain.

Duke University scientists have identified a mechanism in the molecular machinery of the cell that could help explain how neurons begin to falter in the initial stages of Alzheimer’s, even before amyloid clumps appear.

This rethinking of the Alzheimer’s process centers on human genes critical for the healthy functioning of mitochondria, the energy factories of the cell, which are riddled with mobile chunks of DNA called Alu elements.

If these “jumping genes” lose their normal controls as a person ages, they could start to wreak havoc on the machinery that supplies energy to brain cells — leading to a loss of neurons and ultimately dementia, the researchers say.

And if this “Alu neurodegeneration hypothesis” holds up, it could help identify people at risk sooner, before they develop symptoms, or point to new ways to delay onset or slow progression of the disease, said study co-author Peter Larsen, senior research scientist in biology professor Anne Yoder’s lab at Duke.

The dominant idea guiding Alzheimer’s research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause.

The Duke study builds on an alternative hypothesis. First proposed in 2004, the “mitochondrial cascade hypothesis” posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die.

Like most human cells, neurons rely on mitochondria to stay healthy. But unlike other cells, most neurons stop dividing after birth, so they can’t be replaced if they’re damaged.

In Alzheimer’s patients, the thinking goes, the mitochondria in neurons stop working properly. As a result they are unable to generate as much energy for neurons, which starve and die with no way to replenish them. But how mitochondria in neurons decline with age is largely unknown.

Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, Duke neurologist and study co-author Allen Roses (now deceased) identified a non-coding region in a gene called TOMM40 that varies in length. Roses and his team found that the length of this region can help predict a person’s Alzheimer’s risk and age of onset.

Larsen wondered if the length variation in TOMM40 was only part of the equation. He analyzed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer’s-like symptoms with age. He found that in mouse lemurs alone, but not other lemur species, the region is loaded with short stretches of DNA called Alus.

Found only in primates, Alus belong to a family of retrotransposons or “jumping genes,” which copy and paste themselves in new spots in the genome. If the Alu copies present within the TOMM40 gene somehow interfere with the path from gene to protein, Larsen reasoned, they could help explain why mitochondria in nerve cells stop working.

“Alu elements are a double-edged sword,” Larsen said. Once dismissed as selfish or junk DNA, they are now recognized as contributors to the diversity and complexity of the human brain. “They can provide new and beneficial gene functions,” Larsen said. “They have helped humans evolve higher cognitive function, but perhaps at the cost of neuron vulnerability that increases with age.”

When the researchers looked across the human genome, they found that Alus were more likely to be lurking in and around genes essential to mitochondria than in other protein-coding genes.

Alus are normally held in check by clusters of atoms called methyl groups that stick to the outside of the DNA and shut off their ability to jump or turn genes on or off. But in aging brains, DNA methylation patterns change, which allows some Alu copies to re-awaken, Larsen said.

The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules — including the precursor to amyloid — to enter. Larsen used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria’s import machinery to clog and stop working.

Such processes likely get underway before amyloid builds up, so they could point to new or repurposed drugs for earlier intervention, said study co-author Michael Lutz, assistant professor of neurology at Duke.

The TOMM40 gene is one example, the researchers say, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).

The researchers describe the Alu neurodegeneration hypothesis in a paper published online by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“We need to start thinking outside of the box when it comes to treating neurological diseases like Alzheimer’s,” said Larsen, who has filed a provisional patent that focuses on preserving mitochondrial function by keeping Alus in check.

Other authors include Kelsie Hunnicutt, Mirta Mihovilovic and Ann Saunders of Duke. This research was supported by a seed grant from Allen Roses and Duke funds to Anne Yoder.

CITATION: The full text of the research article can be found here in DukeSpace, the university’s online repository of open-access research. “The Alu Neurodegeneration Hypothesis: A Primate-Specific Mechanism for Neuronal Transcription Noise, Mitochondrial Dysfunction, and Manifestation of Neurodegenerative Disease,” Peter Larsen, Michael Lutz, Kelsie Hunnicutt, Mirta Mihovilovic, Ann Saunders, Anne Yoder and Allen Roses. Alzheimer’s & Dementia, Mar. 8, 2017 DOI: 10.1016/j.jalz.2017.01.017

Overview of LBD Symptoms and Treatment – Webinar Notes

Date March 9, 2017

Posted by Robin Riddle

Overview of LBD Symptoms and Treatment – Webinar Notes

Though this webinar from mid-February was titled “Lewy Body Dementia: The Importance of Comprehensive Care and Support,” it’s really an overview of LBD symptoms and treatments.

Brain Support Network volunteer Denise Dagan said that the highlight of the webinar was that one of the speakers, Robert Bowles, has Lewy Body Dementia. She said: “Even though he didn’t speak much, he had a lot to say about what he needs from those around him and how he cares for himself.”

We previously posted about Robert’s blog. See:

www.brainsupportnetwork.org/blogger-who-has-lbd/

What I liked about the webinar was that challenges were presented and strategies offered to cope with those challenges. Also, the webinar gave a good (but fast) overview of LBD symptoms with Robert chiming in every so often as to his experience with certain symptoms.

The webinar organizer was the National Alzheimer’s and Dementia Resource Center (nadrc.acl.gov), a US government center. The speakers’ slides are available in PDF form on the NADRC’s website here:

nadrc.acl.gov/sites/default/files/uploads/docs/508-NADRC-Webinar-LBD%20021517.pdf

And the webinar recording is available on youtube here:

youtu.be/U4noWjXUhQk

By the way, the recording begins after some general info is given about webinar mechanics. And the recording is “captioned” at the bottom of the youtube screen. (Eventually you can learn to ignore the captioning.)

Denise’s extensive notes on the webinar are copied below.

Robin

————————————-

Denise’s Notes from

Lewy Body Dementia: The Importance of Comprehensive Care and Support
February 15, 2017
Webinar Organizer: NADRC
Host: American Society on Aging

Speakers:
Angela Taylor, Lewy Body Dementia Association
Robert Bowles, LBD Advocate and Blogger (Living Beyond Diagnosis)

Objectives:
List 3 symptoms of Lewy Body Dementia (LBD)
2 ways it differs from Alzheimer’s
1 class of drugs to avoid

Dementia, the basics:
Dementia is a general term, not a disease. The definition is cognitive decline severe enough to interfere with daily life. It effects memory, language, executive function, judgement, attention, visuospatial skills, and has behavior symptoms.

LBD is the most mis-diagnosed form of dementia. Often first diagnosed as Alzheimer’s, Parkinson’s disease (PD), or a psychiatric disorder. The second most common form of dementia after Alzheimer’s. Affects 1.4 million in the US, more men than women, and usually between 50-85 yrs old.

LBD includes both Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB).

Symptoms at a glance:
– cognitive issues progress to dementia
– parkinsonism (gait and balance difficulties, stiffness, rigidity, and sometimes tremor)
– behavior changes caused by psychosis
– sleep changes

Importance of early diagnosis:
– Comprehensive clinical care improves quality of life. More responsiveness to Alzheimer’s medications early on.
– Minimize risks for certain medication side effects. People with a diagnosis of LBD should not be given some antipsychotics, benzodiazepines, sedatives, narcotics, medications for PD, anesthesia, etc.

Challenges:
– LBD is complex to diagnose. Presenting symptoms vary and aren’t always well reported. It typically requires a specialist.
– Challenging to treat because of severe medication sensitivities. There are no FDA-approved prescriptions. Its all off-label use.
– It was not on the public’s radar until Robin Williams died, so people are in the learning curve even as the need to advocate for themselves.
– Medication sensitivities in LBD are unfamiliar to healthcare providers, especially emergency rooms (ER) and hospitals. If you have an LBD diagnosis, ask for a neurology consult in the ER, especially if behavior symptoms are presenting themselves.

What to do:
– Self educate about LBD symptoms and treatment
– Prioritize the well-being of the caregiver.
– Connect to the LBD community
– Recognize and reduce stress
– Comprehensive clinical care improves quality of life for both the person with LBD and caregivers.
– You may need to educate your employer if you are still working.

Strategies for Daily Life
Cognitive symptoms: forgetfulness, problem solving/analytical thinking, planning/keeping track of sequences, reduced attention (quick fluctuations of attention), disorganized speech and conversation, loss of sense of direction or spatial relationships between objects (getting lost).

Robert says he notices mostly difficulty with processing of information as it is presented to him, and retrieval of information he needs to be able to respond. Interactions with others needs to be slower for him to understand and formulate his reply.

Strategies to compensate:
– Alzheimer’s medications. Remember, there are none developed for, or approved for LBD.
– Psychological counseling can help with frustration
– Slow down
– Rest (even when mentally tired)
– Adjust your expectations
– Learn to accept help

Robert would like people not to interrupt his train of thought and he needs time to understand you and process his response.

Fluctuation symptoms:
– Concentration and/or alertness
– Episodes of confusion
– Excessive daytime sleepiness

Robert reports emotional fluctuations, too. He can start with a day feeling normal and happy. After awhile he’ll start feeling giddy. Then later brain fog will set in. Eventually he’ll have a ‘sizzled brain’ feeling, And, by the end of the day he’ll have fried brain followed by shut down. This taught him to slow down and rest because it take 2-3 days to recover from fried brain.

Strategies to compensate:
– psycho-stimulants may help
– be flexible & patient
– schedule a nap

Parkinsonism symptoms: rigidity or stiffness; shuffling walk; balance problems; tremor;
slowness of movement; decreased facial expression; change in posture; reduced voice volume and eventually problems swallowing

Robert reports also freezing, and moving backward or sideways unintentionally.

Strategies to compensate:
– Slow down to give brain time to sync with your intended movements so you go in the right direction and not fall while turning or going around corners
– Carbidopa-levodopa may help (but may worsen hallucinations)
– Physical therapy (PT)
– Occupational therapy (OT)
– Speech therapy
– Assess the environment for safety/falling hazards

Autonomic Dysfunction symptoms:
– Dizziness or fainting (orthostatic hypotension – OH)
– Temperature regulation
– Urinary incontinence & urgency
– Constipation
– Unexplained blackouts or transient loss of consciousness, unresponsiveness

Robert’s experience during his early mis-diagnosis of Neuro-cardiogenic Syncope was tons of medications. Once properly diagnosed as OH, he was effectively treated by waist-high stockings

Strategies to compensate:
– Compression stockings, add salt to the diet, adequate hydration
– Dress in layers
– Use a toileting schedule, explore alternates to medications
– Stool softeners, added fiber
– Monitor and call your doctor with concerns

Sleep Disorders symptoms:
– Acting out dreams, sometimes resulting in injury (REM sleep behavior disorder – RBD)
– Insomnia
– Restless leg syndrome

Strategies to compensate:
– You must treat sleep or daytime cognition is worsened!
– Clonazepam or melatonin for RBD
– Assess injury risks. Move bedside tables farther from the bed, put mats or a mattress on the floor beside the bed, etc. to reduce injury risk.
– Find a balance with naps in the daytime so you sleep at night
– Eliminate caffeine after dinner

Behavior & Mood symptoms:
– Hallucinations (audio and/or visual).
– Delusions
– Depression
– Apathy
– Anxiety

Robert says to consider the emotional implications when hallucinations happen.

Strategies to compensate:
– Cholinesterase inhibitors are part of the long-term treatment strategy
– Accept their reality – don’t try to rationalize & reason with them.
– Respond to their emotions, not the hallucination
– Redirect their attention when they are reassured & emotionally not upset
– Consult the physician if behavior suddenly worsens, because it may be something else (over tired, over stimulated, a urinary tract or other infection)

Assessing & Treating Acute Psychosis:
– Assess for pain, infection, other medical causes, re-evaluate med list
– Use cholinesterase inhibitors as part of the long-term treatment strategy
– Review, reduce, eliminate select medications
– Assess the environment
– Use non-pharmacological methods
– Consider use of an antidepressant
– Use atypical antipsychotic medications cautiously and monitor for side effects
– Do not use traditional antipsychotic medications!

How is LBD different from Alzheimer’s?
Different proteins cause the breakdown of normal functioning. In Alzheimer’s, the initial symptom is mainly memory loss, but LBD has more and different initial symptoms.

How is LBD different from Parkinson’s disease?
It is the same protein causing the breakdown of normal functioning. Initial symptom presentation may be the same or different. While cognition is sometimes affected in Parkinson’s disease, dementia is always a factor at the time of diagnosis in LBD.

Preparing for the Office Visit:
Advice for family:
– Be a good detective
– Use LBDA’s Comprehensive Symptom Checklist
– Be a strong advocate

Suggestions for Medical Provider:
– Speak to the patient directly
– Ask what the most bothersome symptoms are – prioritize treating them one by one
– Listen to the care giver for signs of depression and burnout
– Refer to PT, OT, and speech therapy early
– Be proactive with referral to hospice. They can be very supportive of the entire family. Life expectancy is 5-7yrs from diagnosis.

Driving & LBD:
– Increased risk of accidents due to:
– Reduced attention
– Slowed thinking
– Visuospatial skills reduced
– Visual hallucinations
– Motor changes: rigidity, slowed movements, myoclonic jerks

Strategies to get someone to stop driving:
The caregiver should trust their own judgement. If they won’t drive with the person who has LBD, that person should stop driving. Contact the medical provider in advance of an appointment if there are safety concerns. Let the medical provider serve as ’the bad guy.’
Use friends, family and senior services to get around. Don’t forget Uber & Lyft. Gogograndparent.com will book them for you over the phone for a small fee.

Caring for the caregiver, especially if he/she has their own health issue, already. They are at greater risk for: depression, anxiety, isolation, self-doubt, and burnout.

Causes of that greater risk:
– LBD: disrupted sleep, behavioral changes, fluctuations, safety risks
– Delayed diagnosis, especially when the healthcare provider is unfamiliar with LBD
– Low pubic awareness delays diagnosis, and effective treatment.
– Reluctance to ask for and accept help
– No familiarity with community resources, like respite care.

Strategies to compensate:
– Make sure you have an emotional support network: friends, family, an LBD support group and online communities, counselors, church. Have some fun!
– Early referral to community resources. You’ve got to think, “Who’s going to step in if I suddenly become ill?”
– Self-education about LBD
– Embrace their role of patient advocate

Refer Families to Community Resources:
Educate families early about the availability of home health & the importance of respite.
Admission to a long term care facility is generally earlier than with Alzheimer’s, commonly because of the parkinsonism symptoms and behavioral changes.

Questions & Answers

How are people generally diagnosed?
Referral to Neurologist. About 2/3 are done by specialists. Usually, there is a full physical to rule out other causes in behavioral changes. One scan detects change in dopamine producing cells Its not conclusive, but results indicate the Parkinson’s/LBD realm is involved so points in right direction. Autopsy is the only definitive form of diagnosis.

What were Robert’s first symptoms?
Robert was misdiagnosed for about 18 months. He saw eight doctors, a counselor, and psychiatrist. He was catatonic & passing out repeatedly. In retrospect, symptoms probably started five years prior, during a knee replacement. He was not ready for discharge and was hallucinating so he was re-admitted. Two years before retiring his daughter suspected Alzheimer’s, then PD, but it was finally determined to be LBD.

Is there typically memory loss in LBD?
Memory is very good but processing information and retrieval is sometimes painfully slow. Angela suspects people who have more difficulty with memory have a diagnosis of mixed dementia. LBD had many faces. That includes executive function failure or loss of attention that can appear to be memory loss. For all of us, if you don’t use it, you lose it!

Really such a broad range of age (50-85yrs old) at diagnosis?
Usually more seniors, age 70-80 but diagnosis is often years after the first symptoms, so its hard to pin down when it started.

Strategies for behavioral symptoms, like gaining cooperation for showering, taking meds?
Pick your battles. Few things must be done right now. Leave meds for an hour and see where they are when you return. Take yourself out of the equation and focus on the patient’s needs.

“Polypharmacy and the Health of the Elderly” – Lecture Notes

Date March 8, 2017

Posted by Robin Riddle

“Polypharmacy and the Health of the Elderly” – Lecture Notes

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.

“Managing the Change that Nobody Wants”

Date March 8, 2017

Posted by Robin Riddle

Though this blog post was written by a caregiver to someone with Lewy Body Dementia, the thoughts expressed apply to all of us, regardless of neurological condition or role. The author, an organizational development consultant who helps business leaders achieve transformational change, shares what she’s learned about “managing the change that nobody wants.” Here’s a link to the post:

www.avasbutler.com/managing-the-change-that-nobody-wants/

Managing the Change that Nobody Wants
by Ava S. Butler
October 6, 2016

Ava’s advice covers 13 points, some of which are:

* Cherish the beautiful moments and keep them in the forefront of your mind.

* As they say on airplanes, ‘Put your own oxygen mask on before helping others.’

* Be kind to yourself.

* Don’t be afraid of medical terms or doctors that tell you things you don’t understand.

* Talk about your predicament with forthright honesty.

* Know that others are grieving too.

* Do your best to accept your ‘new normal’.

* Help others like you find their way.

* Pray for the best and plan for the worst.

The full blog post is below.

Robin

==================================

www.avasbutler.com/managing-the-change-that-nobody-wants/

Managing the Change that Nobody Wants
by Ava S. Butler
October 6, 2016

I’m an organizational development consultant and I specialize in partnering with business leaders to achieve transformational change. I’ve lead dozens of large scale change projects, most of them moving individuals, teams and organizations to a stronger and better place. I think of change as a positive thing and managing transformational change is my life’s calling.

But not all change is wanted and not all change has a happy ending. My dear husband has Parkinson’s disease and Lewy-body dementia. Its taken over our lives. We fight a battle every day that we will not win. Richard’s ending won’t be fast and it won’t be pretty. It’s costly, time consuming and emotionally draining. No drug will save him and although there is hope for future generations inflicted with these diseases, it’s too late for Richard. We make it the best it can be, but our efforts won’t change the outcome. I’m managing the change that nobody wants.

There’s an irony to unwanted change happening to the change expert. And although my background provides helpful skills and experience, I’m in uncharted waters. I’m learning every day, if I want to or not. And I’ve got a lot more learning to go as we move forward towards our inevitable fate.

Here’s some of what I’ve learned so far. I hope its advice that you can use if you too are dealing with a change you don’t want and can’t avoid.

Cherish the beautiful moments and keep them in the forefront of your mind.

There are plenty of moments of pure hell and they will take over your consciousness if you don’t try hard to balance your thoughts.

For me it’s the tender kiss that still takes my breath away, the gentleness of Richard placing his hand on top of mine, and his beautiful blue eyes on the days they still twinkle. Or the way that Richard’s face lit up when one of his caregiver’s daughters sang him a song she learned in school that day and we all sang the ABC’s song together.

Find joy in the beauty of the world around you.

Take time to acknowledge when the sun is shining, the birds are singing, a hummingbird is outside the window, the leaves are turning or the neighborhood children are playing gleefully in the pool.

Be grateful for the big and small acts of kindness that others show you.

Be vulnerable enough to let people help in ways you would never ask for or even think of. Kindness comes from people you know and also from complete strangers who jump to action when they see you need help.

A few years ago, a man at the Safeway came to our rescue when Richard was hallucinating (due to his Lewy-body dementia) and very afraid. He was running away from me calling for help and I couldn’t get him in our car. The man stopped pumping gas to tell Richard he would help. He told Richard that he was safe and offered him his water as I finally got Richard to take his anxiety medicine. His help allowed Richard to calm down enough that I could get him home. It was early in Richard’s diagnosis and I didn’t have it down yet. I think of that kind man often and am still so grateful for his help.

Do the best that you can every day.

And know that there will be days when your best may not be very impressive. But it’s the best that you can do for that moment. And that’s all you can ask of yourself.

As they say on airplanes, ‘Put your own oxygen mask on before helping others.’

You cannot help others if you are burning out yourself. Take the time to go out with friends, take a walk, or whatever makes you happy or at least gives you a break.

Be kind to yourself.

You will make silly mistakes due to stress, and big mistakes because you didn’t know any better at the time. There are days that you will not find joy in anything and that is to be expected. But try not to beat yourself up.

Don’t be afraid of medical terms or doctors that tell you things you don’t understand.

It’s their job to explain things to you. Ask questions and paraphrase back to ensure understanding. Ask again and again until you feel comfortable understanding the information you need to manage your situation.

Talk about your predicament with forthright honesty.

This lets others talk about it too. Learn to talk about uncomfortable topics that you never thought you would.

Know that others are grieving too.

And they might say or do things that are not helpful to you. But please remember that they are trying to do what they think is best. In the event that someone is not helping you at all with their attitude or advice, don’t hesitate to ask them to give you space.

Turn yourself into a project manager extraordinaire.

Being the primary caregiver means managing lots of moving parts. Be as organized as you can. If this is not your skill set or you are too stressed out or busy to manage the many aspects of your loved one’s life, ask someone you trust to do it for you. And don’t think that once things are set up that they don’t need constant oversight. Situations can get out of hand fast without attention.

For me, I manage a fabulous team of 24/7 caregivers, monitor the cleaning schedule I created, ensure Richard is eating a balanced diet, schedule appointments, and purchase supplies and groceries. I also work and make time to be with my husband. I couldn’t do all that without being a good project manager.

Do your best to accept your ‘new normal’.

There is no point in expecting your life to be like it was before disease struck your life or like the lives of others in your peer group. Your life is different and special now and do what you can to enjoy it. Focus on what you can do instead of what you can’t.

For us, international travel was a big part of our lives, and we can’t do that anymore. We can’t travel together outside our home town of Tucson at all. But we can get in the car with a caregiver and take a trip to our local mountains for an hour.

A good day for Richard isn’t anything like a good day for a normal healthy person. Using traditional standards to measure for a successful day is neither appropriate or gratifying. Measure success by your own customized standards.

Help others like you find their way.

Take the time to share what you’ve learned with others facing the same challenges you face. I’ve learned so much through my journey and have been able to help others who are not as far along in their journey as I am. In turn, they support me too.

Pray for the best and plan for the worst.

Of course you want the best for your loved ones and yourself. Miracles do happen and I pray for and even expect one. But I also must focus on more sobering things like financial planning scenarios and what to do when Richard needs a wheelchair.

I’m not the only one managing the change that nobody wants. There are millions of people just like me, with every imaginable background and story. I hope I can help others, just as so many others are helping me.