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NEUROTRANSMITTERS IN HEALTH AND DISEASE— Overview and Update. Barb Bancroft RN, MSN, PNP CPP Associates Chicago IL www.barbbancroft.com.

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neurotransmitters in health and disease overview and update

NEUROTRANSMITTERS IN HEALTH AND DISEASE—Overview and Update

Barb Bancroft RN, MSN, PNP

CPP Associates

Chicago IL

www.barbbancroft.com

slide2

In the mid-nineteenth century, advocates of physical causes for mental illness recommended bloodletting, purging, cold-water immersion, and various tonics and medications (primarily opium and opium derivatives) as treatment.

  • Others believed that mental disorders were caused by inappropriate mothering; it was thought impossible for patients to recover while at home. Part of the treatment was to place the patients in a mental asylum. To simplify management, many of these patients were restrained in straight-jackets and manacles and chains.
neurotransmitters
NEUROTRANSMITTERS
  • Indolamines

Serotonin (5-hydroxytryptamine, or 5-HT)—the most ubiquitous neurotransmitter of all)

Melatonin

  • Catecholamines (Sympathetic Nervous System)

Dopamine (DA)

Norepinephrine (NE)

  • Acetylcholine (Parasympathetic Nervous System)
  • GABA (Gamma-amino-butyric acid )(inhibitory)
  • Glutamate (excitatory)
  • Nicotine
  • Cannabinoids
the supporting cast
The supporting “cast”
  • Neurotransmitters don’t work as a separate molecule…neurotransmitters need receptors, neurotransmitters need to be metabolized via various enzymes, neurotransmitters need to be “taken back-up” into cells in a timely fashion, the information needs to be transported via pathways…SO, we will be talking about all of the supporting “cast” so to speak…
  • RECEPTORS, ENZYMES, GLIAL CELLS, PATHWAYS
for example serotonin receptors
For example, serotonin receptors
  • Serotonin receptors for example…known as

5-HT (hydroxytryptamine)—and there are MANY of them…5-HT1 through 5HT7, with many subtypes…5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F; 5-HT2A, 5-HT2B, 5-HT2C; 5-HT3; 5-HT4; 5HT-5A; 5-HT6; 5-HT7

  • 5-HT1C does not exist, and the 5-HT5B only exists in mice
serotonin receptors
Serotonin Receptors
  • Drugs that affect serotonin either boost the receptors or block the receptors…agonists or antagonists
  • 5-HT1A—if you activate it you will be anxious; if you block it you will reduce anxiety—Buspirone (Buspar) is a blocker of this receptor
  • 5-HT2C—blocking this receptor results in increased food intake and weight gain; “atypical” antidepressants such as olanzapine (Zyprexa), clozapine (Clozaril)
  • 5-HT1B, 1D, 1F—ifyou boost these receptors vasoconstriction will occur; the “triptans” are used for the treatment of acute migraine headaches**
the triptans 5 ht 1b 1d 1f agonists
The “triptans”--5-HT1B/1D/1Fagonists-
  • Sumatriptan (Imitrex)(64-70% response rate at 2°)

(Treximet—Imitrex (85 mg) + naprosyn (500 mg)

  • Naratriptan(Amerge)(fewer HA recurrences than Imitrex)(45% response rate at 2 hours)
  • Zolmitriptan (Zomig, Zomig ZMT)* (dissolves)
  • Rizatriptan (Maxalt,Maxalt MLT)* (dissolves)
  • Almotriptan (Axert)(dec. chest pain, tightness, pressure)
  • Eletriptan (Relpax)—faster acting than oral Imitrex
  • Frovatriptan (Frova) (longest half-life)(45% response rate at 2°)
warning triptans and coronary heart disease
WARNING: Triptans and coronary heart disease
  • Triptans stimulate the 5-HT1B receptors on coronary arteries and result in vasoconstriction. This may become clinically significant in patients with underlying coronary artery disease or vasospastic disease—the triptans are contraindicated in patients with CAD
  • FYI: More than 50% of neurologists and 75% of headache specialists have migraines
serotonin historical highlights
Serotonin…historical highlights
  • 1st discovered as a protein in serum (sero) in 1948, but the Italians actually initially discovered it in the gut in 1933 and called it “enteramine”
historical highlights
Historical highlights…
  • 1958—Serotonin’s ability to contract a rat’s uterus was found to be antagonized by LSD
  • And, the question begs to be asked… “Who gives a…”
serotonin
Serotonin
  • The bigger question needs to be asked…why were they using LSD in a rat’s uterus?
  • Triggered research into the role of LSD in causing hallucinations (dopamine/serotonin) and into LSD’s schizophrenic-like effect (serotonin/dopamine)
serotonin a k a 5 ht or 5 hydroxytryptamine
Serotonin (a.k.a. 5-HT, or 5-hydroxytryptamine)…
  • Serotonin is the most ubiquitous neurotransmitter of all
  • It’s found in the central and peripheral nervous systems, it is located in the GI tract, platelets
  • ~95% of all serotonin in the body is “enteric” or in the GUT
  • Involved in a wide variety of clinical conditions including…
digression the second brain serotonin and the gut
Digression: The Second Brain...serotonin and the gut
  • Drugs such as SSRIs that increase serotonin in the brain and improve mood, also increase the release of serotonin in the GI tract—increasing gastric motility and the release of serotonin from the duodenum
  • Side effects—nausea and diarrhea (use Imodium)
  • Irritable bowel syndrome—brain-butt connection
  • The histologic changes found in the CNS are also found histologically in the bowel…HUH?
functions of serotonin
Functions of serotonin
  • Happiness
  • Sociability/boosts self-esteem/overcomes shyness
  • Social phobias
  • Makes you full and feel sleepy
  • Impulsive eating disorders such as bulimia
  • Impulse control
  • Helps to control pain pathways
  • Nausea, vomiting, gastric motility
  • Generalized anxiety disorder and panic attacks
  • Aggression
  • Extreme violence
  • Premenstrual dysphoric disorders
  • Migraines
  • Penile erections (ejaculation, specifically)
boosts self esteem overcome shyness
Boosts self-esteem/overcome shyness
  • College fraternity members w/ highest ranking and most friends had 20-40% higher serotonin levels
  • Stroke patients and SRIs (i.e., Prozac)—improved compliance w/ rehab
boosts self esteem
Boosts self-esteem
  • Remove dominant chimpanzee from group
  • Give a subordinate male fluoxetine (Prozac)
  • The subordinate took charge, made friends, organized alliances, and became the top banana.
social phobias off the beaten path phobias
Social phobias—off-the-beaten-path phobias
  • Arachibutyrophobia—fear that peanut butter may stick to the roof of the mouth
  • Erythrophobia—the fear of blushing
  • Peladophobia—the fear of bald people
  • Coulrophobia—a debilitating fear of clowns
  • Bromidrosiphobia—the morbid fear of body odor
  • Albutophobia—the fear of bathing (this phobia reared its ugly head with a vengeance after Alfred Hitchcock’s movie, “Psycho”.)
  • Hellenologophobia—the fear of complex science terminology
plays a role in impulsive eating disorders such as bulimia nervosa
Plays a role in impulsive eating disorders such as bulimia nervosa
  • Bulimia (be aware of girls with Type 1 diabetes and bulimia)
  • Binge-eating disorder
  • Anorexia (?)
  • Boosting serotonin boosts impulse control
  • Helps to control binge eating disorders
  • Fluoxetine (Prozac)
  • Paroxetine (Paxil)
slide19

Levels of serotonin activity are abnormally high in anorexics—linked to feelings of anxiety and obsessional thinking, classic traits of anorexia; dopamine levels are also high— “addicted to starvation” (autoimmune? Genetics?)

anxiety panic attacks
Serotonin—boost mood, boosts self-esteem (“E”, XTC, Ecstasy gives this one a jolt…long term use may deplete the serotonin-containing neurons)Anxiety, panic attacks
aggression premenstrual dysphoric disorder
Aggression--Premenstrual dysphoric disorder
  • A breakdown product of progesterone, allopregnanolone, acts on receptors for GABA—has a calming effect; fluoxetine (Prozac/Sarafem) specifically increases allopregnanolone
penile erection
Penile erection
  • Low serotonin is presumed to be a major part of the cause of premature ejaculation
  • SSRIs are used to treat this condition
serotonin and depression
Serotonin and depression
  • “The FDA this week approved the first-ever transdermal patch for the treatment of depression. Simply remove the backing and press the patch firmly over your mother’s mouth.” ---Tina Fey, on Saturday Night Live (March 2006)
serotonin estrogen and menstrual migraines
Serotonin, estrogen and menstrual migraines
  • During low estrogen states such as menses (the sudden drop of estrogen triggers migraines)
  • Or during the placebo week of oral contraceptives, serotonin levels decrease and the headaches occur
  • How about using an estrogen patch 7 days prior to menses, or OC without the placebo week?
  • (Lybrel (Wyeth)—first FDA-approved low-dose combination oral contraceptive taken 365 days per year)
  • During high estrogen states, ie, pregnancy, serotonin rises and headaches decrease
mirror neurons
Mirror neurons
  • Is happiness contagious?
  • Is depression contagious?
  • Mom’s and babies…
  • Nature vs. Nurture
serotonin and depression1
Serotonin and depression
  • Depressed women have 53% less serotonin in the pleasure centers of their limbic system than men
  • Increased rates of classic depression in women and this gender difference starts at puberty
what do we eat
What do we eat?
  • In addition to increasing serotonin in the brain, chocolates (boost)anandamide—a substance that closely resembles marijuana (“ananda” in Sanskrit means “bliss”…
  • Bliss is a 1 lb bag of M & M’s…
slide29

Carbohydrates facilitate the entry of tryptophan (the amino acid required to produce serotonin) into the brain

  • CHO’s also increase the release of insulin from the pancreas and bingo, you put on weight
  • Especially with more than 125 grams of carbohydrates per day
implications for low carb diets
Implications for low-carb diets
  • Dr. Atkin’s, South Beach
  • Is she really that happy? NOOOOOOOOO
  • Females without carbs—no energy, depressed, and constipated with halitosis
  • Men love their red meat – why? (meat contains tyramine, the precursor to the catecholamines—norepinephrine and dopamine)
the numbers don t lie
The numbers don’t lie…
  • From the early 1960s to 2002, the mean weight for men and women aged 20-74 increased 24pounds and the mean height increased approximately 1 inch
  • During 1999-2002, the mean weight of men over 20 years of age was approximately 190 pounds and the mean height was approximately 5’9”
  • Among women, the mean weight was approximately 163 pounds and the mean height was approximately 5’4”

(US Dept. of Health and Human Services, CDC, National Center for Health Statistics, 2004; Available http://www.cdc.gov/nchs/data/ad/ad347.pdf)

weight loss drugs
Weight loss drugs
  • The weight loss drugs target the satiety center in the hypothalamus—boost serotonin that tells you – “stop eating, you’re full”
  • Redux and Fenphen increased serotonin in the satiety center
  • Meridia (sirbutamine)—prevented the re-uptake of serotonin in the satiety center—weak; removed from the market on October 8, 2010 due to the risk (ever so slight) of severe cardiovascular events
drugs for weight loss
Drugs for weight loss…
  • OFF LABEL use of some drugs—metformin (Glucophage), topiramate (Topomax)
  • Some new drugs are awaiting approval by the FDA
  • NEW possibility but not FDA approved yet…lorcaserin, a selective serotonin 5-HT2C agonist, is in phase III clinical trials—helps to lose weight and MAINTAIN weight loss
  • NO increased risk for valvular heart disease like fenphen
guys don t crave carbs they have plenty of self esteem
Guys don’t “crave carbs”…they have plenty of self-esteem…
  • They think they look like this today…and they DID in the 1960’s
serotonin makes you happy in the mesolimbic system of the brain
Serotonin makes you happy in the mesolimbic system of the brain
  • The number ONE class of drugs prescribed today for depression are the serotonin reuptake inhibitors (SRIs) or the SSRIs Selective SRIs
the sri s serotonin reuptake inhibitors
The SRI’s (serotonin reuptake inhibitors)…
  • 1987—the first selective serotonin reuptake inhibitor was “unleashed” and we all know that drug as fluoxetine, Prozac (Lilly) (longest t½)
  • Sertraline (Zoloft)(1992)—shortest t½; excellent choice for elderly depressed patient; may also be useful for mild irritability and aggression
sris serotonin reuptake inhibitors
SRIs (Serotonin Reuptake Inhibitors)
  • Paroxetine (Paxil)(1992) ++drug interactions; adrenergic effects=tremor—14.7% @ 40 mg/d); most anticholinergic
  • Citalopram (Celexa)(2000)—most selective affinity for HT receptors; useful for mild irritablity and aggression
  • Escitalopram(2002)(as above) (Lexapro)(#12 of the top selling drugs in 2009)**fewest SE of all SRIs—new use: reduce the number of hot flashes (TAMOXIFEN)
new antidepressant approved
New antidepressant approved
  • VilazodoneHCl (Viibryd)—a combined selective SRI and sertonin 1A receptor partial agonist
  • Rx—Major Depressive Disroder
  • No sexual dysfunction, no significant weight gain
  • Nausea, diarrhea, vomiting, insomnia
  • Boxed warning for an increased risk of suicide in 18-24 y.o.
depression in children
Depression in children
  • Prozac is still the only drug approved by the FDA for the treatment of depression in children and adolescents
  • Prozac has a longer t½ life; Makes withdrawal more gradual and, it also
  • Keeps levels steady if a dose is missed (teenagers in particular often miss or skip doses)
  • More later…
give antidepressants time to work 3 5 weeks but monitor closely during this time
Give antidepressants time to work! 3-5 weeks…but monitor closely during this time
  • Why does it take so long for anti-depressants to work?
  • How long should your patients stay on antidepressants?
  • (P.S. escitalopram/Lexapro may ease depressive and anxiety symptoms more quickly than the other SRIs—in some cases by the end of week one)
neurogenesis 1998
Neurogenesis--1998
  • Dr. Spickerman
  • Antidepressants
  • Statin drugs
  • What else boosts neurogenesis?
  • Exercise and meditation
other antidepressants inhibit the re uptake of both serotonin and norepinephrine snris
Other antidepressants inhibit the re-uptake of both serotonin and norepinephrine--SNRIs
  • Other antidepressants inhibit the reuptake of both serotonin & norepinephrine and are called the SNRIs (Venlafaxine/Effexor)(1997); duloxetine (Cymbalta) and desvenlafaxine (Pristiq)(2005)
  • Used for depression
  • Other indications are numerous—more later
p s the old antidepressants known as tcas tricyclic antidepressants
P.S. the “old” antidepressants known as TCAs (tricyclic antidepressants)
  • Amitriptyline (Elavil)
  • Nortriptyline (Pamelor, Norpramin)
  • Also boost serotonin and norepinephrine but they are not referred to as SNRIs…
  • More later about the clinical uses of the “old” TCAs…
other antidepressants
Other antidepressants
  • Wellbutrin (bupropion)—boosts dopamine (energizing and also boosts sex drive; no weight gain)
  • Remeron (mirtazepine)—boosts norepinephrine (lots of weight gain)
the sris side effects
The SRIs—side effects
  • Increasing serotonin may result in decreased dopamine
  • Dopamine gives you some zip to your doo-dah in the bedroom
  • SRIs may result in anorgasmia, loss of libido and premature ejaculation
  • What can you do? Zoloft—short half-life
  • Add Wellbutrin (or switch to Wellbutrin) or amantadine (Symmetrel) to boost dopamine
  • Yohimbine? NO; OTC’s?
  • Estratest?
other side effects of ssris lesser known but important
Other side effects of SSRIs—lesser known, but important
  • Inhibit platelets—bleeding
  • Bruxism—increase serotonin, decrease dopamine results in jaw clenching at night
  • RLS—increased serotonin, decrease dopamine, increases leg movement
  • SIADH—dilutional hyponatremia
a new eating disorder not yet officially recognized by the dsm but
A new eating disorder (not yet officially recognized by the DSM, but…)
  • Orthorexia—obsession about eating the “right thing”, the “perfect diet”—fixate on eating foods that make you feel pure and healthy
  • Overly concerned about preparation techniques—washing foods multiple times and sterilizing utensils
  • Food obsessions hinder ADL; strict rules and beliefs about food may lead them to become socially isolated; orthorexics may become intolerant of other people’s view about food and health (Dr. Steven Bratman)
slide48
Other conditions with decreased serotonin…(and increased norepinephrine)—poor self-esteem, lack of impulse control
  • Chronic alcohol abuse (also decreases dopamine)
  • Chronic child abuse (mental, physical, sexual)--PTSD
  • Closed head injuries--PTSD
  • anabolic steroids (“roid rage)
  • Low cholesterol levels--aggression
  • Exposure to lead as a child--aggression
  • When serotonin re-uptake inhibitors are used, serotonin levels increase, thinking becomes clearer
notes on the use of sris
Notes on the use of SRIs
  • Used for patients with OCD, binge-eating, PTSD, aggression
  • Child abuse/spousal abuse—the P’s ↓ aggressive levels by 25%; gives time to reflect—reflective delay; size up situation and prevents immediate reaction
do anti depressants work for everyone
Do anti-depressants work for everyone?
  • NO
  • Psychotherapy is definitely beneficial
  • What else can you do?
get out in the sun
Get out in the sun!
  • Vitamin D and depression—reduced 25 (OH)D levels –depressed patients averaged 37 ng/L, non-depressed—46 ng/L
  • Depression rates have increased over the last century
  • Humans have reduced their light exposure
slide53
How?
  • Via urbanization (tall buildings and pollution reduce UVB)
  • Industrialization (working inside reduces UVB exposure)
  • Cars (glass totally blocks UVB)
  • Clothes (even light clothing blocks UVB)
  • Sunblock
  • Misguided medical advice to never let the sunlight touch your unprotected skin
  • (Vitamin D Council, National Institutes of Mental Health, 2011)
will vitamin d supplements help
Will vitamin D supplements help?
  • Ongoing research using D3 (cholecalciferol), not D2 (ergocalciferol)
  • 400 IU and 800 IU have been shown to positively improve affect
  • Larger doses have been shown to improve depression scales
  • More research…could help, doesn’t harm
exercise
Exercise…
  • Boosts serotonin
  • Boosts endorphins (for up to 24 hours after exercise)
  • Builds new neurons
anti depressants and pain management neuropathic pain
Anti-depressants and pain management (neuropathic pain)
  • Boosting serotonin

and NE in the descending pain pathways helps treat neuropathic pain

  • Amitriptyline (Elavil)
  • Nortriptyline (Norpramin)
  • Venlafaxine (Effexor)
  • Duloxetine (Cymbalta)*
  • *has just been approved for the treatment of musculoskeletal pain)
other drugs for neuropathic pain
Other drugs for neuropathic pain
  • And then, there’s always gabapentin (Neurontin) and pregabalin (Lyrica), and topiramate (Topamax)—more on these drugs later
  • Neurontin and Norpramin together have been shown to be quite effective when neither drug works alone (Lancet. September 2009)
serotonin 5 ht 3 receptors and n v
Serotonin 5-HT3 receptors and N & V
  • 5-HT3 in the CTZ (chemoreceptor trigger zone of the brain stem) is responsible for vomiting from chemo and post-anesthesia
  • 5-HT3 in the duodenum is responsible for nausea– “the organ of nausea”
  • Anticipatory nausea and vomiting
serotonin antagonists for 5 ht 3
Serotonin antagonists for 5-HT3
  • The “setrons” for chemotherapy, postanesthesia-induced, and migraine-induced nausea and vomiting
  • Granisetron (Kytril)
  • Ondansetron (Zofran)*
  • Dolasetron (Anzemet)
  • Palonesetron (Aloxi)
  • + decadron
  • *approved for morning sickness in pregnancy
irritable bowel syndrome
Irritable bowel syndrome
  • Too much serotonin? Diarrhea-predominant

Rx: alosetron (Lotronex)—5-HT3 blocker

  • Too little serotonin? Constipation-predominant
  • RX. Lubiprostone (Amitiza)

Rx: tegaserod (Zelnorm)—a 5-HT4 partial agonist was approved to increase motility of GI tract (March 30 2007—d/c’d due to CV events—can still get from drug company if nothing else works)

st john s wort the name
St. John’s Wort…(the name?)
  • “St. John’s wort is the most common herb involved in drug interactions.”
  • (Bonakdar RA. Herb-drug interactions: what physicians need to know. Patient Care 2003; January: 58-69.)

Tatro DS, ed. Drug Interaction Facts: Herbal supplements and Food. St. Louis, MO. A. Walters Kluwer Co; 2004; also available at www.factsandcomparisons.com

digression st john s wort for depression
Digression: St. John’s Wort for depression
  • Does it work? Yes, it has been shown to be superior to placebo.
  • May boost serotonin, norepinephrine by mild MAO inhibition; may also boost GABA and dopamine to varying degrees
  • Also appears to decrease cytokines and hormones of the stress response (IL-6 and cortisol) that may be responsible for mild depression—INTERESTING EFFECT as it’s the ONLY drug that has shown to reduce cortisol’s effects in the brain—decrease stress? IMPROVE DEPRESSION AND MEMORY
  • ??Effective for mild to moderate depression…not severe
  • Do NOT use with other anti-depressants—especially SSRI’s
serotonin syndrome
Serotonin syndrome
  • Adverse drug reaction caused by an increase in serotonin levels and stimulated central and peripheral postsynaptic serotonin receptors
  • Drugs associated with serotonin syndrome include SSRIs, SNRIs (serotonin-norepinephrine reuptake inhibitors—venlafaxine/Effexor, desvenlafaxine/Pristiq, duloxetine/Cymbalta), MAO inhibitors, TCAs, opiates, OTC cough meds, drugs of abuse, drugs for weight loss, and herbal products (St. John’s wort)
  • Also associated with medication withdrawal
  • 60% of patients present within 6 hours of medication initiation, overdose, or change in dosage; 74% present within 24 hours (Evans)
a few notes on pediatric depression
A few notes on Pediatric depression
  • The only FDA-approved medication for the treatment of childhood depression (7+ age) is fluoxetine (Prozac) starting dose 10 mg/day
  • Do more kids commit suicide on anti-depressants? FDA required warning labels on antidepressants in 2004 after a small but statistically significant increased risk of suicidal thoughts and/or attempts in children and adolescents taking antidepressants
  • Studies did NOT show increased suicidal completion, nor did they establish the base rate of suicide that would have occurred without treatment
a few notes on pediatric depression1
A few notes on Pediatric depression
  • Studies since that ruling indicate that antidepressants are efficacious in the treatment of pediatric depression and the risks of increased suicidality do NOT outweigh the direct patient benefits of these medications (Garzon DL, Nelson J, Figgemeir M. Management of childhood depression. TheClinical Advisor 2009 (October).
a few notes on pediatric depression2
A few notes on Pediatric depression
  • Mood improvement does not take place for a month or more, while side effects tend to appear immediately. This can worsen the sense of hopelessness and contribute to the perception that the treatment is worse than the illness
  • Meds increase energy level but the feeling of hopelessness does not lift, and the patient finds the strength to carry out a suicide plan
  • The child who with major depression is actually showing the first signs of bipolar illness and will swing toward mania when treated with an antidepressant
  • The number of new bipolar diagnoses in kids has jumped 4,000 percent between the years of 1994 and 2003. Dr. Mark Olfson, Columbia University, NYC)
gaba gamma amino butyric acid
GABA (gamma-amino-butyric-acid)
  • She is “inhibitory”…
  • NO, NO, NO
  • Simple amino acid
  • Similar in structure to the class of drugs known as the BZ’s…benzodiazepines
  • Valerian and the GABA-BZ receptor (“stink weed”) and the Pied Piper
benzodiazepines
Benzodiazepines
  • Benzodiazepines (anti-anxiety drugs)—first introduced in the 60s as “mother’s little helpers” (Librium w/ slogan— “Whatever the diagnosis—Librium”)
  • How do they work? GABA-BZ receptor; GABA is inhibitory and “calms” the brain
  • Cause sedation, reduce anxiety; muscle skeletal relaxation; anticonvulsant effects
  • Long-acting vs. short-acting
anxiolytics hypnotics
Anxiolytics/hypnotics

Benzodiazepines— “zepams” and “zolams”

*Diazepam—Valium (t1/2 20-100 h)

*Flurazepam—Dalmane(40-114)

*Quazepam—Doral (25-115)

Clonazepam—Clonapin (18-50 h)

Lorazepam—Ativan (10-20)

Oxazepam—Serax (5 -20)

Temazepam—Restoril (10-40)

Triazolam—Halcion (2.5)

*t ½ is your age in HOURS…

**chlordiazepoxide (Librium is also a BZ—wrong last name tho’—half life as long as diazepam)

gaba pentin neurontin fanatrex gabarone
GABA-pentin (Neurontin, Fanatrex, Gabarone)
  • The “Swiss-Army Knife” of neurology
  • Approved for use in 1994 as an anticonvulsant
  • In 1996, research on other clinical uses began to appear in the literature
  • “off label” use for neuropathic pain in the late 1990s
  • Approved for neuropathy and other chronic neuropathic patin syndromes in 2002
  • Major depressive disorder
  • 2nd generation GABA agonist--pregabalin
1 st approved for seizure disorders
1st approved for seizure disorders
  • Glutamate is excitatory
  • GABA is inhibitory
seizures anti convulsants and gaba
Seizures—anti-convulsants and GABA
  • Gabapentin (Neurontin)
  • Topiramate (Topamax)—increase inhibitory effects of GABA and blocks excitatory effects of glutamate
  • Tiagabine (Gabatril filmtabs)—inhibits GABA re-uptake
  • Valproic acid—Depakote, Depakene, Depacon, Stavzor
a note on valproic acid
A note on valproic acid
  • Not only an anti-convulsant, but also a mood stabilizer—PTSD, (bipolar patients)
  • Survival benefit on the battlefield by preventing acetylation in cells, causing certain “survival pathways” to be switched on
  • Pig research—drained 60 per cent of blood, subjected them to injuries seen on battlefield; gave all of the pigs saline; gave some of the pigs valproic acid, others a blood transfusion and the rest untreated
  • Only 25% of the pigs that received saline survived 4 hours, the typical time it takes to get hospital treatment, while 86 percent of those injected with valproic acid lived
  • Big fat no-no in pregnancy—birth defects; autism
more anti convulsants
More anti-convulsants
  • Phenobarbital—enhances GABA-mediated chloride influx through inhibitory neurotransmitter channels
  • Phenytoin (Dilantin)—reduces sodium, potassium and calcium currents across neuronal membranes
  • Carbamazepine (Tegretal)—same as above (also used with pain syndromes); Equetro is extended release carbamazepine)
  • Lamotrigine (Lamictal)—MOA? May stabilize neurons and reduce glutamate release (also known as a mood stabilizer)
pain syndromes and neurontin
Pain syndromes and Neurontin
  • CRPS (complex regional pain syndrome)
  • Peripheral neuropathy
  • Pain and spasticity of MS (Botox and Baclofen for spasticity too)
  • Trigeminal neuralgia
  • Migraines (Botox, face lift)
  • PHN (postherpetic neuralgia)--shingles
  • Myofacial pain
other clinical uses of neurontin
Other clinical uses of Neurontin
  • Radiation myelopathy
  • RLS (restless leg syndrome)
  • ALS (Lou Gehrig’s disease)
  • Periodic leg movements
  • Fibromyalgia
  • Depression
  • Bipolar disease
  • Hot flashes
  • Inhibits “echo-like” effect in damaged nerves
  • Boosts GABA inhibition in the interneurons in spinal cord
other anticonvulsants
Other anticonvulsants…
  • Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro)—seizure disorders, bipolar disorder, trigeminal neuralgia

also classified as a mood stabilizer

  • Topiramate (Topamax, Topiragen)(2006)—seizure disorders, migraine prevention (investigations are ongoing for the treatment of alcoholism, obesity, reducing binge eating, PTSD, OCD, smoking cessation, neuropathic pain, cocaine dependence); being studied in combination with phentermine to forma a drug called Qnexa to Rx obesity
gaba and dopamine in chronic alcoholics
GABA and dopamine in chronic alcoholics
  • Dopamine is like a toddler-run, run, run; gives you energy
  • GABA keeps dopamine in check
  • Chronic alcoholics have decreased dopamine—no energy
  • ETOH takes the place of GABA
  • When alcoholics don’t have access to booze, dopamine “rebounds”
  • Causes the DTs (delirium tremens)
alcohol withdrawal syndrome
Alcohol withdrawal syndrome
  • The DTs (delirium tremens)
  • Medical emergency with sx of hallucinations, confusion, disorientation, generalized seizures and pronounced autonomic activity
  • Tachycardia, hypertension, hyperthermia, tachypnea (rapid breathing), tremors
alcohol gaba and dopamine
Alcohol, GABA, and dopamine
  • Normally, GABA (Mom) inhibits dopamine (toddler—energy)
  • Chronic alcohol intake takes the place of GABA and chronically keeps dopamine levels low (no energy)
  • When alcohol is removed, it takes dopamine 3-5 days (or less) to rebound—
  • “Whoa!” where’s mom?
  • There is NO mom as GABA has been chronically depressed from alcohol
  • Dopamine rebound results in the DTs with s & s of catecholamine excess
how do you treat the dts
How do you treat the DTs?
  • The GABA-BZ (benzodiazepine) receptor—boosting the GABA receptor with BZ’s during alcohol withdrawal puts the brakes on dopamine rebound; benzodiazepines “act” like GABA
  • RX: “Mother’s little helpers”--Lorazepam (Ativan)—1 mg initial dose (range 2-4 mg); diazepam (Valium)—5 mg initial dose (10-20 mg range), chlordiazepoxide (Librium)—25 mg is initial dose (50-100 mg range); oxazepam (Serax)—15 mg is initial dose (10-30 mg range)
alternatives
Alternatives
  • Short-acting BZs without active metabolites (oxazepam/Serax) or lorazepam (Ativan) are acceptable alternatives in the elderly or in patients with advanced liver disease
  • Non BZ anticonvulsants such as carbamazepine (Tegretal), valproic acid (Depakote, Depakene), gabapentin (Neurontin) and topiramate (Topamax) have also been used in detoxification
norepinephrine
Norepinephrine
  • Gives you energy
  • Boosts mood
  • Lack of norepinephrine = anhedonia (the lack of interest in day-to-day activities)
  • Drugs that boost norepinephrine make you happy and give you energy (amitriptyline/ Elavil; reboxitine (Edronax)
  • Drugs that block norepinephrine have the opposite effect– lipid-soluble beta blockers (propranolol, timolol, metoprolol, carvedilol) and Prednisone (long-term) for example--anhedonia
  • Helps control pain in the descending pain pathways
  • Fight-flight response and aggression
why petey the pit bull
Why Petey the pit bull?
  • Higher levels of L-tyrosine, the precursor to norepinephrine, the transmitter of aggression
  • “fight/flight” system
  • Nothing can terminate a pit bull attack
  • Increased release of endorphins—may be addictive at high doses which may explain why they will continue to fight over and over again
norepinephrine1
Norepinephrine
  • Initially large doses of Prednisone cause euphoria due to the release of norepinephrine in large amounts
  • Eventually with continued use, norepinephrine can be depleted
  • “steroid psychosis”
  • Predisone also boosts norepinephrine in your appetite center
  • Amitriptyline (Elavil) boosts N.E. in the appetite center
  • Mirtazepine (Remeron) does too.
chronic stress and norepinephrine
Chronic stress and norepinephrine
  • Long term elevations of cortisol (chronic stress), and perhaps short term bursts (acute stress) can permanently change the structure of the hippocampus
  • Cortisol is neurotoxic--direct toxicity to the neurons of the hippocampus
  • PTSD
lithium eskalith cr eskalith lithobid
Lithium (Eskalith CR, Eskalith, Lithobid)
  • 1st used for gout in the 1800s as it was able to dissolve uric acid crystals; because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders; first used to treat mania in 1870s
  • 1st used in 7-Up in 1929 as a medicinal ingredient of a refreshment beverage; marketed specifically as a hangover cure (Bib-Label Lithiated Lemon Lime Soda)
  • Mood stabilizer
  • decreases norepinephrine release, increases serotonin synthesis
  • Resets biological clock
  • Boosts neurogenesis
who put the dope in dopamine
Who put the dope in dopamine?
  • What does dopamine do in the brain?
  • Gives you a huge burst of energy, alertness, and attentiveness (along with norepinephrine in the brain)
  • Too much can cause anxiety, fidgety (think cocaine users)
  • Excess? addiction, psychosis, hallucinations (schizophrenics)
  • Boosts sex drive
  • Bombards the reward system which contributes to its addiction potential. In other words—wowWEEE! That felt good, let’s do it again, and again, and again
  • Movement—get up and get moving; control of voluntary movements and postural reflexes
so what can we become addicted to
So what can we become addicted to?
  • Alcohol
  • Nicotine
  • Methamphetamine
  • Cocaine
  • Morphine
  • Hydrocodone
  • Oxycontin
  • Heroin
  • psilocybin (magic mushrooms); PCP;
  • peyote (mescaline);
  • LSD— “Lucy in the Sky with Diamonds”
  • Methadone
  • Sex
  • French fries
french fries you shriek
“FRENCH FRIES!!!” You shriek…
  • Addictions to food activate the brain in the same way that the brains of cocaine addicts are affected when they think about their next dose. The mere display of food significantly increases metabolism in the areas associated with addiction.
  • Who throws on the brakes for Mickey D’s FRIES?
dopamine and the reward system
Dopamine and the reward system
  • A critical component of the reward system is dopamine
  • All addictive drugs release it—and some increase dopamine much more than any natural stimuli
  • Stimulating dopamine is the common denominator of all addictive drugs and behaviors—even tho’ each drug has its own unique effects—the high of alcohol is different than the high of cocaine, heroin or methamphetamine.
  • Dopamine is critical for “wanting” something, not necessarily “liking” it…
  • With continued abuse of a substance, dopamine increases not as a result of the behavior but in anticipation of the behavior
memory and the reward system
Memory and the reward system
  • The reward system also has the ability to encode cues to help you repeat the experience
  • You remember the night you met the love of your life—the room, the clothes, the smell, the meal…and you look forward to repeating this event (in fact, those initial few years are drenched in dopamine…AND THEN???)
  • Oxytocin is released…the hormone of monogamy and comfort
let s get back to addiction
Let’s get back to addiction
  • Unfortunately, this “memory” becomes a problem to the addict—cues that have no particular importance to survival or pleasure—such as a line of white powder, a cigarette, or a bottle of brown liquid—activate the same reward system
  • With repeated use, the circuitry adapts to dopamine, and normal pleasures, such as sex, become less pleasurable compared to the drug.
  • Addiction is one of the most powerful memories we can have--relapses are common
  • For example, nicotine cessation usually take 5 to 7 attempts
the addict s brain has been reorganized or hijacked
The addict’s brain has been reorganized or “hijacked”
  • Drug seeking responses are initiated according to certain cues, therefore it’s critical to help the addict avoid those cues
  • Remove the addict from the environment where he has become addicted (30 days is not enough)(airport bars for example)
  • Addict has to re-learn impulse control (30 days is not enough)
  • The addict needs to be retrained to inhibit impulses toward drug use as they occur (30 days is not enough)
early exposure to drugs and alcohol
Early exposure to drugs and alcohol…
  • More and more evidence points to “when” you start addictive behaviors increases your risk of lifelong addictions
  • Robert Downey, Sr. gave Jr. drugs and marijuana at age 6—thinking it was “cute”…
  • “I’m allergic to alcohol and drugs—I break out in handcuffs. –Robert Downey, Jr.
by the way
By the way…
  • the White House and drug “CZAR” still consider marijuana as the “gateway” drug…(cheaper drug, more accessible to young kids, feel that it’s not dangerous, so they will try harder drugs?? Higher risk in the first place?)
  • Studies have shown that tobacco smoking is a better predictor of concurrent illicit drug use than smoking marijuana
  • Even tho’ our problems with prescription drug abuse and methamphetamine are escalating out of control, we’re spending millions to find the one “pot” plant in the basement of an 82-year-old grandmother
a note or two on marijuana
A note or two on marijuana
  • At low to medium doses it reacts with anandamide—(means “bliss” in Sanskrit)
  • Other effects at low to medium doses—decreased blood pressure, relaxation, reduced coordination, sleepiness, disruptions in attention, altered time and space, illusions and the “munchies”
  • Anti-motivational syndrome
  • Pantoprazole (Protonix) use can test positive for THC
digression the teenage brain
Digression: The Teenage Brain
  • Dopamine system of rewards is developing during adolescence
  • Dopamine is responsible for the “high”—wow, this feels good…let’s do it again!
  • Just how good? Sex and crystal meth (in a minute)
  • Adolescents become addicted faster and with lower doses of addictive agents including oxycontin, meth, marijuana, alcohol, and nicotine
  • hypersensitive to the value of experiences,
d3 receptors and addiction
D3 receptors and addiction
  • D3 receptors are the “addiction” receptors—imaging studies have shown that the number of D3 receptors in the brains of alcoholics are decreased (is this the chicken or the egg?)
  • Does it take more alcohol to stimulate fewer receptors?
  • If the level of receptors can be raised, will the alcoholic decrease their alcohol intake? The answer is yes, at least in rats.
other transmitters involved in addiction
Other transmitters involved in addiction
  • Glutamate
  • Serotonin
  • Endorphins— “endogenous morphines”— “runner’s high”…(Candace Pert and the discovery of morphine receptors/Bill Moyers and Healing and the Mind)… “Why Bill…you would be surprised…”
boosting dopamine in the treatment of parkinson s disease can boost addictive potential
Boosting dopamine in the treatment of Parkinson’s disease can boost addictive potential
  • Parkinson’s disease results from a deficiency of dopamine in the striatal area of the brain; treating PD involves either boosting or replacing dopamine
  • Dopamine boosters such as pramipexole (Mirapex) and ropinirole (Requip) primarily stimulate dopaminergic receptors (D1) and the release of dopamine from any remaining dopamine containing neurons
  • Side effects—hallucinations (D2), gambling addictions, food addictions, sexual addiction (become sexual pests)(D3)
addiction and dopamine agonists
Addiction and dopamine agonists
  • Pramipexole (Mirapex) is the biggest offender; 1.5% of the patients on Mirapex become pathologic gamblers, alcoholics, gluttons, and sexual pests
  • Develops within first month and up to 30 months; usually dramatically clears within one month of stopping drugs
  • These are the same drugs used as 1st line Rx—RLS (restless leg syndrome) and can lead to addictive behaviors
well i started cause i heard that crystal meth was great for sex how great might that be
“Well, I started ‘cause I heard that crystal meth was great for sex…” How great might that be?
  • Well, harken back to your last orgasm…hmmmm…
  • The POO (plain’ ol’ orgasm) releases 10,000 molecules of dopamine as the molehill moves…
  • The methamphetamine induced orgasm releases 70,000 molecules and the earth moves, mountains move, volcanos erupt and of course, you want to do it again…and again…
  • The addiction potential is enormous—only 10% of the people who try alcohol will ever become alcoholics whereas, close to 95% of those who try methamphetamine over an entire weekend will become addicted to the drug
meth effects depletion of dopamine producing cells over the year rapid aging
Meth effects: Depletion of dopamine producing cells over the year; rapid aging
  • Potent vasoconstrictor—hypertension, strokes, acute coronary syndromes
speaking of methods of ingestion
Speaking of methods of ingestion
  • Swallowing pills or ETOH—produces a slow rise in the brain concentration (depending on how fast you drink of course, and the amount, and gender, etc.)—pills must be digested, absorbed, and metabolized/detoxified by the liver; marijuana brownies
  • Smoking a substance—much quicker route to the brain—7 to 9 seconds
  • IV drug use—to the brain in 2 seconds; numerous veins used; dorsal vein of the penis; infections (HIV, HCV, staphylococcus, endocarditis, GABHS)
it s not just youngsters on drugs
It’s not just youngsters on drugs…
  • Estimated 1.7 million baby boomers addicted to drugs
  • By 2020 the number will increase to 4.4 million
  • First generation to have a high incidence of using recreational drugs
  • Long-term risks of pot?
  • LSD and mescaline? Flashbacks?
  • Cocaine? Chronic heart disease? Acute MIs?
  • Heroin? Hypertension, HIV, liver and pulmonary diseases (67% of heroin users smoke)
speaking of methods of ingestion1
Speaking of methods of ingestion…
  • Mucous membranes (as in Witche’s brew-- “deadly” nightshade plant”, henbane (scopolamine for “twilight sleep”, mandrake and on occasion, hemlock—teenagers and alcohol-soaked tampons; champagne enemas; rubbing cocaine on the gums; snorting cocaine and meth (insufflation)
  • Anesthesiologists have the highest rate of addiction of all MDs
  • Nicotine via the rectum for other reasons in the old days—nicotine receptors in the bowel trigger bowel movements—surgeons and cigars
dopamine receptors
Dopamine receptors
  • D1 receptors (boosting D1 initiates movement and reduces prolactin secretion) and D2 receptors (psychosis/hallucinations)
  • Bromocriptine (Parlodel) boosts D1 receptors in the hypothalamus/pituitary to inhibit the release of prolactin –was commonly given to lactating moms in the old days to dry up breast milk production; the problem was the movement disorder that it triggered
d2 receptors
D2 receptors
  • D2 receptors are the key targets in dopamine blocking agents, but blocking the D1 receptor can cause disabling side effects…Parkinsonism, or hyperkinesia and galactorrhea
  • The “old” antipsychotics (such as chloropromazine/Thorazine (1952) *and haloperidol/Haldol, Mellaril (thioridazine), fluphenazine (Prolixin), Trilafon (perphenazine), thiothixene (Navane),trifluoperazineStelazine)—reduced hallucinations and psychosis, but induced a “statue-like, zombie” state and the patients were shooting breast milk across the room!
  • *Serendipitous observation that this drug improved symptoms when give as a pre-anesthetic agent
the newer atypical antipsychotics
The newer “atypical” antipsychotics
  • Thought to improve negative symptoms, hence the term “atypical”—but no difference between old and new w/ negsx
  • Efficacy is the same—SIDE EFFECTS are different
  • Block 5-HT2C serotonin receptors (helps to decrease hallucinations and psychosis) but are also specific for D2 receptors
  • Need to block at least 65% of D2 receptors for antipsychotic efficacy; greater than 70% blockade increases S.E.
the newer atypical antipsychotics1
The newer “atypical antipsychotics”
  • Blocking 5-HT2c serotonin receptor increases weight gain; increased susceptibility to insulin resistance and type 2 diabetes
  • P.S. Schizophrenics have ALWAYS had a higher risk of insulin resistance and diabetes LOOONG before these drugs were used…these drugs just help to unmask it
atypical antipsychotics mixed d2 5 ht 2a antagonists
“Atypical” antipsychotics—mixed D2/5-HT2A antagonists
  • Clozapine (Clozaril)(’90)—best of the bunch as far as reducing symptoms and improving negative symptoms. “It’s rare to see dramatic responses in schizophrenia, but those patients who have the diagnosis and yet who present as completely healthy—in terms of the way they dress, talk and so on—those are the people who are likely to be on clozapine—Dr. Dost Ongur, Clinical Director, McLean Hospital, Harvard Medical School; interviewed in The Carlat Psychiatry Report, December 2009)
atypical antipsychotics
“atypical antipsychotics”
  • olanzapine (Zyprexa)(’96),
  • risperidone (Risperdal)(’93),
  • quetiapine (Seroquel)(’97),
  • ziprasidone (Geoden)(‘01),
  • olanzapine + fluoxetine = Symbyax (approved for depressive episodes associated with bipolar disorder);
  • paliperidone ER (Invega)
atypical antipsychotics1
“atypical antipsychotics”
  • aripiprazole (Abilify)(’02)
  • Dopamine system stabilizer (partial agonist at D2 and 5-HT1A/ full antagonist at 5-HT2A)
  • Iloperidone (Fanapt)—less effective than risperidone (Risperdal) and haloperidol (Haldol)
  • Asenapine (Saphris)—sublingual for acute mania—mouth numbness
atypical antipsychotics2
Atypical antipsychotics
  • Weight gain= Clozapine (Clozaril)(biggest offender) and #2 is Olanzapine (Zyprexa); 10 weeks/10 pounds
  • Agranulocytosis w/ Clozapine—1st 3 months; 1/10,000
  • Risperidone w/ intermediate wt gain, ziprasidone (Geodon) with least weight gain Clozapine>olanzapine>risperidone/paliperidone>que-tiapine>ziprasidone/aripiprazole
atypical antipsychotics3
Atypical antipsychotics
  • As the risperidone (≥6mg)/paliperidone/ziprsidone dose increases, so do the extrapyramidal system (EPS) side EPS effects
  • But not quetiapine (Seroquel) or clozapine (Clozaril)
antipsychotic use in the elderly and mortality rates
Antipsychotic use in the elderly and mortality rates
  • There is a large increased mortality in patients with AD who are prescribed antipsychotic meds
  • Evidence of modest short-term benefits of antipsychotic Rx for neuropsychiatric sx, however, at 2 years survival was 46% in the antipsychotic group and 71% in the placebo group; at 3 years the survival was 30% in the antipsychotic group and 59% placebo
  • Overall, the risk of death was 42% lower in the placebo group than the antipsychotic group
tardive dyskinesia
Tardive dyskinesia
  • Metoclopramide (Reglan) is the most common cause of drug-induced movement disorders (FDA 2/26/09)
  • High risk groups? Elderly females (over 65) for longer than 3 months
  • Involuntary, repetitive movements of extremities, tongue protrusion, grimacing, puckering/pursing of lips, impaired movement of fingers)
the older antipsychotic drugs
The “older” antipsychotic drugs
  • Did you also know that schizophrenics, in general, are at risk for extrapyramidal symptoms, even WITHOUT drug therapy?
  • Tardivedyskinesia was described in the late 19th century, over 50 years before the discovery of the first antipsychotic med; approximately 40% of schizophrenics will develop TD in the absence of treatment (Fenton)
temperature regulation and dopamine
Temperature regulation and dopamine
  • Patients on neuroleptic drugs (central dopamine blockers) tend to have lower basal temperatures (always complaining of “feeling cold”)
  • Schizophrenics may be wrapped in a blanket in the summer
  • Lower basal temperatures—need to re-consider what is “febrile” in a patient on neuroleptic drugs
dopamine and the gi tract
Dopamine and the GI tract
  • Dopamine inhibits GI peristalsis
  • Acetylcholine boosts GI peristalsis
  • Balance between the two is 50:50
  • Patient with gastroparesis?
  • Block dopamine with metoclopramide (Reglan) allows unopposed acetylcholine and peristalsis
  • Problem: Reglan is lipid-soluble and crosses BBB; blocks dopamine in the basal ganglia and can cause a drug-induced Parkinsonism and other movement disorders
dopamine too much too little
Dopamine—too much? Too little?
  • Too little can cause depression (chronic alcoholism)
  • Too little can cause too little movement (think Parkinson’s disease or parkinsonism from drugs—like metoclopramide/Reglan)
  • Too much can cause too much movement—chorea/athetosis (Huntington’s chorea)(Tourette’s syndrome)(Tardive dyskinesia)
too much dopamine
Too much dopamine
  • Huntington’s chorea
  • Crack cocaine
  • Carbon monoxide poisoning
  • Tourette’s syndrome
movement disorders
Movement disorders…
  • The basal ganglia—
  • Paired nuclei at the base of the brain
  • 50:50 balance between acetylcholine and dopamine
  • Gamma-amino butyric acid (GABA) keeps dopamine in check

Caudate nucleus

Globus pallidus

Substantia nigra

Subthalamic nucleus

the basal ganglia
The BASAL GANGLIA…
  • Control of movement, initiation and cessation of movement
  • Postural reflexes—the righting reflex
  • Dopamine levels decrease with aging gradually—we all slow down
  • Dopamine reserves, in particular, decrease with advancing age, and medications that may affect dopamine pathways are likely to trigger extrapyramidal effects (Timiras )
clinical symptoms
Clinical symptoms
  • Anosmia (loss of smell)(may predate Parkinson’s disease by a decade)
  • As can REM sleep behavior disorder—in which dreams are accompanied by excessive movement (portends neurodegenerative disorders – including Parkinson’s disease, Lewy body dementia, or multiple system atrophy--that manifest up to 25 years later) (Boeve B, Neurology , August 10, 2010.
parkinson s disease
Parkinson’s disease
  • Resting tremor (70%)—unilateral or bilateral
  • Rigidity (vs. spasticity of stroke patients)
  • Loss of voluntary movements (spontaneous)
  • Bradykinesia (check gait)
  • Postural instability (sternal push)
  • Progression to dementia is common (40-60%)
parkinson s disease1
Parkinson’s disease
  • By the time signs and symptoms of PD emerge, approximately 50% of the dopaminergic neurons in the substantianigra have degenerated, and more than 60-80% of dopamine has been lost.
  • Treatment is to replace dopamine
  • The clinical benefit of levodopa/carbidopa varies with the duration of chronic levodopa treatment
  • Initially, symptom control is very good and most patients retain the benefits even if a dose is missed
  • However, wearing off motor fluctuations can begin as early as several months after initiation of treatment
slide129

Dopamine agonists—not as potent; bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip)

  • Side effects: gambling addiction, sexual pests
  • Used for restless legs syndrome as well
glutamate
Glutamate
  • The excitatory neurotransmitter
  • Has been determined to play a major pathological role in the neurodegenerative disease ALS (amyotrophic lateral sclerosis) or Lou Gehrig’s disease
  • May play a major role in schizophrenia along with GABA—diffusing into the tissues surrounding the synapse may kill neurons; glial cells are responsible for clearing out glutamate and GABA; glial cells may not be functioning normally
  • Plays a role in migraines?
possible new treatment not yet fda approved memantine namenda for migraines
Possible new treatment, not yet FDA approved: Memantine (Namenda) for migraines
  • Females have a lower threshold for a phenomenon called cortical spreading depression (CSD)—bursts of intense electrical activity across the cortex resulting in migraines
  • Memantine (Namenda) blocks CSD
  • Clinical trial reported in the September 2007 issue of the Journal of Headache Pain found the more than 50% of the patients reported that their headaches were half as frequent and of much less severity (Charles A, Brennan K, et al.)
  • Use with Alzheimer’s drugs such as Aricept
the flu pregnant women and schizophrenia
The flu, pregnant women, and schizophrenia
  • Mom’s – GET THE FLU SHOT
  • Higher risk of schizophrenia in fetus’ exposed to the flu at critical periods of development
  • Cortical thinning and enlarged ventricles
how long do drugs stay in the body
How long do drugs stay in the body?
  • Blood and urine tests are most reliable; hair samples are not
  • THC (the substance in marijuana responsible for the high) is detected in the blood for 4 to 8 hours in frequent users and 3 to 4 hours in non-frequent users
  • 9-carboxy THC (product of metabolism of THC) is detectable in urine and blood for much longer periods of time
  • Frequent users? 2 weeks up to 3 months in heavy users
  • Infrequent users? Up to 10 days
  • Can passive smoke cause + blood tests? For a day or so with heavy smoke exposure in an enclosed room; most tests have intentionally high standards to avoid false + results due to incidental ingestion

Cocaine metabolites in urine for up to 3 days…some drugs can have a false + as can some diseases

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