Transcript Alpha receptors, Beta receptors, Kappa Receptors—It’s all

Alpha receptors, Beta receptors,
Kappa Receptors—It’s all GR℮℮K to
me…
Barb Bancroft, RN, MSN
[email protected]
August 4, 2010
Receptors, receptors, receptors…
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Alpha receptors (alpha one and twos)
Beta receptors (beta ones and twos)
Kappa receptors
Mu receptors
Muscarinic receptors
Nicotinic receptors
And…
Receptors, receptors, receptors…
• Dopaminergic receptors (D1 and D2)
• Histaminergic receptors (H1 and H2)
• Serotonergic receptors (15 different receptors!
90-95% in the GUT)
• Melatonin receptors
• Hormone receptors—thyroid, cortisol, estrogen,
progesterone, testosterone
• Receptors, receptors, receptors….they’re
EVERYWHERE!
Let’s chat about
neurotransmitters/hormones/receptors…
• Consider the proverbial lock and key example
• The transmitter/hormone is the key (also known
as a ligand), the receptor is the lock
• The transmitter/hormone/key/ligand is the
agonist (booster) which provides a signal to the
cell to trigger a specific function or,
• the ligand can be an antagonist (or blocker) of
that lock and the receptor cannot get the signal
• The key can either partially fit the lock and boost
it (partial agonist) or block it (partial antagonist)
Let’s start with hormones…the chain
of events
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Hypothalamic—pituitary-end organ axis
HPA—hypothalamic-pituitary-adrenal axis
HPO—hypothalamic-pituitary-ovarian-axis
HPT—hypothalamic-pituitary-thyroid-axis
Get the drift?
Releasing factor/hormone from the
hypothalamus interacts with receptor on pituitary
to trigger the release of a stimulating or inhibiting
hormone which in turn interacts with a receptor
on the target organ
The hierarchy of messaging in the
endocrine system
• The hypothalamus is, millimeter for
millimeter, the most powerful subdivision in
the brain.
• It weighs about 4 grams and constitutes no
more than 1 percent of total brain volume
• However, it is the critical link between the
cerebral cortex, the limbic system, and the
hormonal out put of the “master gland”, the
pituitary
Pituitary gland
• Pituitary comes from the Latin pituita, meaning
“phelgm,”, also related to the Greek ptuō, meaning “I
spit.” The Greek word, obviously, is vividly imitative and
is the forerunner of the expletives “Ptooey!” and
“Phooey!”
• The Greeks and Romans believed that the brain
secreted a mucoid substance that was discharged
through the nose (ie, “snot”)
• …this notion was finally nixed in the 17th century but
the name pituitary stuck
• Infundibulum (funnel) attaches the pituitary gland to
the brain
But you actually have two separate pituitary
glands—the anterior and the posterior pituitary
• The anterior pituitary is actually an outpouching
of the posterior pharynx of the mouth (GI tract)—
backs up through the craniopharyngeal canal and
“sticks” itself to the posterior pituitary
• The posterior pituitary is a direct extension of the
hypothalamus vial the infundibulum and
therefore is part of the nervous system
• Go figure. Two different germ layer origins—
ectoderm for the posterior and endoderm for the
anterior.
Anterior and posterior pituitary
• To release the hormones from the posterior
pituitary (oxytocin* and vasopressin/ADH), the
hypothalamus sends a direct message via
neuronal pathways of the infundibulum
• To release hormones from the anterior pituitary,
the hypothalamus has to send a message via the
capillary system (hypophyseal portal system)
• Sheehan’s necrosis of the anterior pituitary
gland—infarction of the anterior pituitary during
delivery (sudden loss of blood via hemorrhaging)
Oxytocin
• The first peptide ever to be replicated outside the
body was oxytocin (1953). It’s released from the
posterior pituitary gland during childbirth to bind
with receptors in the uterus, where it stimulates
uterine contractions to help “expel” the baby
• Synthetic oxytocin, as we all know, is Pitocin
• HISTORICAL HIGHLIGHT: As early as 1902, people
knew there was something in crude extracts of
farm animal pituitary glands that could be used
by obstetricians to aid women who had been in
labor for a prolonged period
Women and oxytocin
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Tend and befriend
Cuddly, momma-earth hormone
Milk let-down response
Uterine contractions during orgasm
Hormone of monogamy
• Men and oxytocin? HELLO???
The hierarchy of messaging in the
endocrine system
• Gonadotropin-releasing hormone/factor—Gn-RF,
or Gn-RH from the hypothalamus sends a
message to the anterior pituitary to release LH
and FSH; the hormones released by the anterior
pituitary go to receptors on the target organ—
one of gonads (ovary and/or testicles)
• Thyrotropin RF/RH to the anterior pituitary to
release TSH; TSH stimulates the thyroid to release
thyroxine
• Easy peasy…
Whoa, not so fast…
• Inhibiting factors can also be released; a real
important one is PRL-IF…of course, this makes
perfectly good sense; who would want to release
prolactin (pro-lactation) on a daily basis?
Especially if one IS NOT breast feeding…
(…dopamine plays a role in the release of these
hormones from the pituitary via D1 receptors—
more later)
• A common tumor of the pituitary gland is a
prolactinoma and of course, one of the
symptoms is un-called for galactorrhea
And then there are mega-molecules released
from the hypothalamus/pituitary…
• Proopiomelanocortin…
• Gotta little bit of everything in it…
• Opio – enkephalins (“in the head”—
endogenous opiates)
• Melano—melanocyte stimulating hormone
• Cortin—corticotropin releasing factor
How about other “keys”?
Neurotransmitters…
• Indolamines
Serotonin (5-hydroxytryptamine, or 5-HT)—the most
ubiquitous neurotransmitter of all)
Melatonin
• Catecholamines (Sympathetic Nervous System)
Dopamine (DA)
Norepinephrine (NE)
Epinephrine (E)
• Gamma-amino-butyric acid (inhibitory)
• Glutamate (excitatory)
• Acetylcholine (Parasympathetic Nervous System)
• Nicotine
• Cannabinoids
And ALL of the above have receptors either
throughout the body, in the brain, or BOTH
• SEROTONIN for example…
• 90-95% of all serotonin is actually produced in
the GUT “enteric nervous system” (when it was
first discovered by the Italians in 1933 it was
called “enteramine”
• 1st discovered as a protein in serum in 1948, and
was called “sero” for serum and “tonin” for it’s
vasoconstricting properties (who makes it in
serum? Why, none other than platelets…)
• …only 5-10% is found in the brain but it packs a
powerful punch in the mesolimbic system
Many receptors can be involved in body functions—
Nausea and vomiting, for example
Many receptors can be involved in body functions—
Nausea and vomiting, for example
• Numerous receptors are located in 3 major areas
(central and peripheral ) for nausea and vomiting:
1) the vomiting center of the brainstem (known as
the TVC, or true vomiting center where all
vomiting eventually goes through), and
2) the CTZ (the chemoreceptor trigger zone in the
area postrema of the fourth ventricle of the
brain, the major chemosensory organ for emesis
and is usually associated with chemically
induced vomiting), and
3) the duodenum of the GI tract.
What receptors?
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Cholinergic
Histaminergic
Dopaminergic
Opiate receptors
Benzodiazepine receptors
Serotonin receptors
Substance P
Cannaboid receptors
Lots of etiologies
• GI disturbances—obstructions, gastroparesis, PUD,
pancreatitis, pyelonephritis, cholecystitis, cholangitis,
hepatitis, acute gastroenteritis (viral, bacterial)
• Neuro—increased ICP, migraine headache, vestibular
disorder
• Metabolic—ketoacidosis, Addison’s disease, uremia
• Psych causes—psychogenic, anxiety, anorexia, bulimia
• CV diseases—MI (inferior/diaphragmatic/right
ventricle)* CHF, radiofrequency ablation
Lots of etiologies
• Therapy-induced causes—cytotoxic
chemotherapy, radiation therapy, theophylline
preparations, anticonvulsant preparations,
digitalis preparations, opiates, antibiotics,
anesthetics
• Drug withdrawal—opiates, benzodiazepines
• Miscellaneous causes—pregnancy, noxious
odors
CHEMO: major cause—who makes you throw
up the worst? The emetogenicity of
chemotherapeutic agents
• Highest risk – greater than 90% of all patients
will vomit taking carmustine, cisplatin,
cyclophosphamide ≥ 1500 mg/m²,
dacarbazine, dactinomycin, mechlorethamine,
streptozotocin—ANTICIPATORY N & V
• Moderate risk (30 to 90%)—carboplatin,
cytarabine > 1 g/m², daunorubicin,
doxorubicin, epirubicin, idarubicin, ifosfamide,
irinotecan, oxaliplatin
Emetogenicity of chemotherapeutic
agents
• Low risk (10 to 30%)—bortezomib, cetuximab,
cytarabine < 1 gm/m², docetaxel, etoposide,
fluorouracil, gemcitabine, methotrexate,
mitomycin, mitoxantrone, paclitaxel, pemetrexed,
topotecan, trastuzumab
• Minimal (less than 10%)—bevacizumab,
bleomycin, busulfan, 2-chlorodeoxyadenosine,
fludarabine, rituximab, vinblastine, vincristine,
vinorebine
• (2004 Perugia International Antiemetic
Consensus Conference)
So who blocks what?
• Histamine 2 antagonists—the usual suspects;
cimetidine (Tagamet HB), famotidine (Pepcid AC),
nizatidine (Axid AR), ranitidine (Zantac)—to block
the acid that can sometimes trigger the
duodenum and cause N and V
• Substance P/neurokinin 1 receptor antagonists—
aprepitant / Emend--is the first approved
member of this class of drugs; part of a multiple
drug regimen for N and V associated with highdose cisplatin-based chemo
So, who blocks what?
• Antihistaminic-anticholinergic—cyclizine
(Marezine), dimenhydrinate (Dramamine),
diphenhydramine (Benadryl), hydroxyzine
(Vistaril, Atarax), medlizine (Bonine, Antivert),
scopolamine (Transderm Scōp),
trimethobenzamide (Tigan)
• Used for simple N and V (motion sickness, inner
ear problems)…adverse reactions can be
miserable tho’--in the elderly—a mouth like the
Mohave desert, confusion, blurred vision, urinary
retention, and possibly tachycardia
So, who blocks what?
• Serotonin (5-HT3) antagonists—dolasetron/Anzemet,
granisetron (Kytril), ondansetron (Zofran),
palolnosetron (Aloxi)—number one choice for
chemotherapy-induced vomiting from the CTZ
(sertonin released in response to chemo, not only from
the CTZ but also from the duodenum causing the
intense nausea)
• Combine the 5-HT3 antagonist with a little dab of
dexamethasone/Decadron and the chemo-induced N
and V is somewhat tolerable (easy for me to say…as I’m
not the one with N and V from cisplatin)…but as an old
Peds Onc Nurse…
So, who blocks what?
• Phenothiazines -- chlopromazine(Thorazine),
prochlorperazine (Compazine), promethazine
(Phenergan), thiethylperazine (Torecan)
• Cannabinoids—dronabinol (Marinol), nabilone
(Cesamet)— chemo for cancer
• Butyrophenones—haloperidol (Haldol),
droperidol (Inapsine)
• Benzodiazepines – alprazolam (Xanax), lorazepam
(Ativan)
• Dopamine blocker—metoclopramide
(Reglan)(more later on side effects)
Name that transmitter…
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A naturally occurring plant alkaloid, the color of pure water
Can be obtained anywhere without a prescription
Acts almost as quickly as cyanide
Death ensues only a few minutes after swallowing a dose as small
as sixty milligrams
• Continued use in smaller, less toxic doses quickly leads to tolerance
and dependency
• 1988 report—the pharmacological and behavioral processes
determining addiction to it are “similar to those that determine
addiction to drugs such as heroin and cocaine.”
• And the answer is……….
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If you said NICOTINE, you are correct!
• Stimulates the acetylcholine receptor in the
brain that researchers named the nicotinic
receptor
• Induces more nicotinic receptors
• Nicotine induces alertness and arousal
• Increases mental efficiency—possible clinical
use in AD in the future as a transdermal skin
patch (smoker’s actually have less Alzheimer’s)
• Tourette’s syndrome, ulcerative colitis
Historical highlights
• The tobacco plant is native to the Americas
• Europeans discovered it on their trips to the Americas
and brought it back to Portugal and Spain in the 16th
century; they viewed it as a miracle cure for everything
from headaches to dysentery. As tobacco use spread,
health concerns increased, and by 1573 the Catholic
Church had forbidden smoking in Churches.
• Nobody stopped smoking and the Industrial Revolution
led to mass production of the perfect nicotine delivery
system—the cigarette; delivers the hit of nicotine to
the brain in 7 seconds
Nicotine
• Not only stimulates nicotinic receptors, it also triggers
the release of endorphins and dopamine in the
mesolimbic system of the brain
• Pleasure, addiction and reward are the result
• Also inhibitory transmitters are released, such as
GABA, to reduce anxiety, lessening of irritation and
aggression, suppression of appetite and weight loss
• And paradoxically, excitatory glutamate is released that
influences memory and learning
• Tolerance develops and the smoker increases the
number of cigarettes smoked, thus developing a
physical dependence on cigarettes
IS THIS A HEALTH PROBLEM?
• The first manufactured cigarette appeared in
the U.S. in the 1860’s and by 1884, James B.
Duke was producing almost a BILLION
cigarettes per year
• P.S. DUKE University is researching the medical
benefits of nicotine—rather ironic, eh?
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How do you stop smoking?
• Willpower? Cold turkey?
• Easier said than done…
• Usually takes 5 or 6 attempts…
How do you stop smoking?
• Chantix (varenicline)—partial nicotine agonist;
binds to nicotine receptors but stimulates
them LESS than nicotine; also blocks some of
the pleasurable effects that patients get when
they smoke
• Start it one week before the quit date; titrate
dose to effective levels
• $2.00 per dose—much LESS than a pack of
cigs
Other methods
• Buproprion (Zyban)—MOA? Unknown, but by
itself cessation rates are 35%; with nicotine
replacement (gum, patch), cessation rates are
39%
• Varenicline (Chantix)—six month abstinence rate
is 71% -- adverse events—agitation, hostility,
depression, suicidal ideation, suicidal behavior
• 98 suicides on Chantix; 14 on Zyban
• Don’t discourage use – encourage monitoring and
specific questions about suicide, esp. in patients
with pre-existing psych disorders (Tonstad)
Serotonin
More 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 al rat’s…”
• The bigger question needs to be asked…why
were they using LSD in a rat’s uterus?
• LSD’s schizophrenic-like effects (serotonin and
dopamine excess) were discovered shortly
thereafter…
Serotonin (a.k.a. 5-HT, or 5hydroxytryptamine)…
• Serotonin has 16 different receptors
throughout the body
• Serotonin is produced from the amino acid
tryptophan in the diet
• Serotonin is involved in a wide variety of
clinical conditions including…
Functions of serotonin…
• Happiness
• Boosts self-esteem (guys have more serotonin to being
with/overcomes shyness
• Social phobias
• Makes you full and feel sleepy
• Eating disorders such as bulimia
• Helps to control pain pathways
• Nausea, vomiting, gastric motility
• Generalized anxiety disorder and panic attacks
• Premenstrual dysphoric disorders
• Impulse control
• Extreme violence
• Migraines
Serotonin receptors—5-HT
(hydroxytryptymine)
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5-HT1, 5-HT2, 5-HT3, 5-HT4
Subtypes—5HT1A, 1B, 1C, 1D, 5-HT2A, 2B…
Get it?
5-HT1A—if you boost it you will be anxious; if you block it you
will reduce anxiety—Buspirone (Buspar) blocks this receptor
• 5-HT2C—blocking this receptor results in increased food intake
and weight gain; antipsychotics such as olanzepine (Zyprexa),
clozapine (Clozaril); interestingly so does the oldest
antipsychotic—Thorazine…
• 5-HT1B/1D—if you boost it vasoconstriction will occur; the
“triptans” are 5-HT1D agonists/boosters given during the acute
phase of migraine headaches**
So where does the pain come from?
• Two theories
1) Pain is caused by the cortical spreading
depression that triggers the brainstem and
trigeminal nucleus pain pathways
2) Pain may originate in the brainstem centers for
pain—the nucleus raphe, the locus coeruleus,
and the periaqueductal gray matter; these three
centers are responsible for controlling the flow
of sensory information—light, noise, smell,
pain—that reaches the cortex
So, where does the pain come from?
• These 3 nuclei normally send their inhibitory
message to the trigeminal nerve network that
says do not fire
• If these nuclei are firing abnormally this may
trigger the spreading depression in the cortex or
subcortex and subsequently activate the
trigeminal nucleus
• The network of neurons that stems from the
trigeminal nucleus carry pain signals from the
meninges and from the blood vessels that supply
the meninges
How do we treat the acute migraine
headache? The TRIPTANS
• Three potential mechanisms of action:
1) cranial vasoconstriction
2) peripheral neuronal inhibition
3) inhibition of transmission through the
trigeminocervical complex in the brainstem
These mechanisms inhibit the effects of
activated nociceptive trigeminal afferents and
control acute migraine attacks
Who are the triptans? 5-HT1B/1D receptor
agonists for migraines
• Sumatriptan (Imitrex) and Treximet (sumatriptan
with naproxen)
• Naratriptan (Amerge)(fewer HA recurrences than
Imitrex)
• Zolmitriptan (Zomig, Zomig ZMT)*
• Rizatriptan (Maxalt,Maxalt MLT)*
• Almotriptan (Axert)(dec. chest pain, tightness,
pressure)
• Eletriptan (Relpax)—faster acting than oral Imitrex
• Frovatriptan (Frova)(longest half-life)
• *The “melt in your mouth”—dissolves on tongue; no
need for water
Triptans and coronary heart disease
• Triptans can 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—contraindicated in CAD
• However, common triptan side effects include
tightness, heaviness, pressure or pain in the
chest, neck and throat—these are not associated
with ECG changes and are not caused by coronary
vasoconstriction in the majority of patients
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.)
Famous Migraineurs…
• Elizabeth Taylor
• Joan of Arc
• How about men? Julius Caesar, Napoleon,
Thomas Jefferson, Ulysses Grant, Sigmund
Freud*, Claude Monet, Elvis Presley
• *Freud was a psychiatrist and a neurologist.
More than 50% of neurologists and 75% of
headache specialists have 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
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 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 aka SSRIs
• Is happiness contagious?
• Is depression contagious?
• Mom’s and babies…
• Nature vs. Nurture
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)
• 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
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)
Serotonin synthesis
• The amino acid, tryptophan, is the precursor
to serotonin (found in abundance in turkey,
chicken)
• Direct correlation between the amount
consumed in the diet to the amount
synthesized in the CNS via tryptophan
hydroxylase--but only if you can get it across
the blood brain barrier
• How can you do that?
EAT CARBOHYDRATES…
• The CHO load triggers the release of insulin
from the pancreas; the insulin bolus makes all
of the “other” amino acids enter the
peripheral tissues, leaving the door open for
tryptophan to enter the brain
• But it needs a pile of mashed potatoes to do it
Implications for low-carb diets
• Dr. Atkin’s, Dr. Agatston (South Beach)
• Is she really that happy? NOOOOOOOOO
• Females without carbs—no energy,
depressed, constipated with halitosis
• Men love their red meat – why? (meat
contains tyramine, the precursor to the
catecholamines)
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)—prevents the re-uptake of serotonin
in the satiety center—weak
• NEW and exciting…lorcaserin, a selective seratonin 5-HT2C
agonist, is in phase III clinical trials—helps to lose weight
and MAINTAIN weight loss…coming to a prescriber’s pad
near you shortly
• NO increased risk for valvular heart disease like fenphen
Chocolate also boosts serotonin…
• In addition to increasing serotonin in the
brain, chocolates trigger anandamide—the
only natural marijuana receptor-stimulating
chemical discovered at this point
• “ananda” in Sanskrit means “bliss”…
• Bliss is a 1 lb bag of M & M’s…
• Marijuana and the “munchies”
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, 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)
St. John’s Wort…
• “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: 5869.)
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
• 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 depression…not moderate to
severe; Do NOT use with other anti-depressants—
especially SSRI’s
A few notes on medical marijuana…dronabinol
(Marinol) and nabilone (Cesamet)
• Stimulate the feeding centers in the brain—
used to treat anroexia and weight loss in
cancer and AIDS patients
• FDA-approved for N and V from chemotherapy
(as mentioned earlier)
• Nabiximois (Sativex in Canada) is approved as
an oromucosal spray as adjunctive treatment
of central neuropathic pain in MS patients;
phase III trials for intractable cancer pain
The autonomic nervous system
• What is this nervous system for?
• The preservation of the species and selfpreservation activities
• It “automatically” does this without you thinking
about it…
• You run when you’re scared, you eat when your
hungry, you have sex because your NETflix movie
didn’t arrive in the mail and there’s nothing to
watch on TV, you reproduce so that your children
can support you when you’re old
Functions of the autonomic nervous
system? The 4 F’s
• Sympathetic Nervous System (SNS)—nerves
originate from the thoracolumbar areas of the
spinal cord
• “fight-flight” system—self-preservation when
in danger
• Let’s say you decide to visit Chicago at 3 a.m.
and you take a “wrong-turn”…what’s gonna
happen to you?
Fight-Flight—adrenalin is flowin’
• Your pupils are going to dilate
• Your heart is going to pound
• Your bronchioles are going to open up to gasp
for air
• The large arteries in the arms and legs are going to
dilate to get more blood for running and pumping
action
• Piloerection, sweaty palms, and sweaty pits
• What do your bowels WANT to do?
Functions of the autonomic nervous
system—the 4 F’s
• The parasympathetic Nervous System is the
“vegetative” system…day to day activities for
preservation of the species and selfpreservation…Feeding activities and F@!king.
activities.. (erection, but not the grand finale,
ejaculation; ejaculation is a sympathetic
phenomenon)
• Parasympathetic—nerves originate from the
craniosacral areas of the brainstem and spinal
cord (cranial = specific cranial nerves)
Just remember…the systems OPPOSE
one another
• If the sympathetic nervous system says
INCREASE the heart rate, the parasympathetic
system says, NO, decrease the heart rate
• Sympathetic? BRONCHODILATE? NO, the
parasympathetic says BRONCHOCONSTRICT
• Sympathetic? Pupils dilate or
parasympathetic, pupils constrict
• So simple, yet so confusing…more later
Parasympathetic Nervous System (PNS)—
craniosacral output--acetylcholine
… lacrimal gland—tear secretion (CNVII)
… circular muscle of the iris—constriction of the pupil (CN III)
… ciliary muscle—accommodation for near vision (CNIII)
…Salivary glands—secretion of watery saliva (CN VII and IX)
… heart—rate and force reduced—slows heart rate (CN X)
… lung airways—bronchoconstriction and bronchosecretion (CN
X)—especially at night
…GI (CN X) – tightens LES, stimulates peristalsis
…sacral output- relaxes urinary sphincter, contracts bladder wall,
contracts uterus, causes an erection, stimulates intestine (X)
Muscarinic receptors (M1,2,3)
• Refers to the parasympathomimetic receptors in the
peripheral nervous system (nicotinic receptors are in the
brain and acetylcholine interacts with these receptors in
the brain; nicotinic receptors are also in the peripheral
nervous system, but most peripheral parasympathetic
effects are mediated by the muscarinic receptors)
• Origin of the muscarinic term is in the Latin musca, “a fly.”
• Prototype is muscarine, a natural alkaloid isolated in 1869
from a species of poisonous mushroom called Amanita
muscaria. Amanita is an ancient Greek name for a kind of
fungus, muscaria refers to its hairy appearance.
Muscarinic
• The Latin muscarium means, literally, “pertaining
to flies,” but to the Romans a muscarium was
specifically a sort of flyswatter made up of hairs
from a horse’s tail.
• The pulp of the fungus was also smeared on to
house walls to act as an fly insectiside (agaric)
• So, the hairy mushroom (red with white spots—a
favorite of fairy-tale illustrators) that looked a
little like a flyswatter was found to contain a
poisonous alkaloid that was given the name of a
flyswatter.
Drugs can either BOOST acetylcholine receptor
or block acetylcholine receptors
• Let’s say you have a problem with urinary
retention…can we give you something to relax
the smooth muscle sphincter? Absolutely, it
acts just like acetylcholine and it’s name
should receive the NOBEL prize…
• DUVOID aka, Urecholine--bethanechol is the
generic name, and in Canada the brand name
is Myotonachol
The complex mechanism of voiding
• It’s not as simple as you think…voiding is a
complex mechanism with sympathetic
(hypogastric and pelvic nerves), parasympathetic
input via muscarinic and nictoinic receptors, and
somatic input to striated muscle of the bladder
neck and external urinary sphincter via the
pudendal nerve (acetylcholine, again)
• Blocking the somatic pudendal nerve that
releases acetylcholine can tighten up the external
sphincter and the botulinum toxin (BOTOX) has
been shown to treat incontinence in some cases
Of course, the anti-cholinergic effects of drugs
are also helpful for overactive bladder
• Tighten urinary sphincter (urinary retention)
• Useful in women with overactive bladders,
BUT the systemic side effects can be
debilitating
73
Drugs for OAB (overactive bladder)—
anticholinergic effects
Anti-muscarinics with grade A efficacy:
 Tolterodine (Detrol LA); fesoterodine (Toviaz)
 Darifenacin (Enablex); solifenacin (Vesicare)
 Trospium (Sanctura)
Mixed actions with grade A efficacy
 oxybutynin (Ditropan)(Gelnique—topical
gel)(Oxytrol patch)
 propiverine
 (Prescriber’s Letter, June 2009;16(6):36
74
Anti-cholinergic drugs—side effects
•
•
•
•
•
•
Confusion
Pupillary dilation (blurred vision, glaucoma)
Tachycardia (angina, possible MI)
Decreased salivation (dry mouth)
Decreased peristalsis in GI tract (constipation)
Tighten urinary sphincter (urinary retention)
75
Anti-cholinergic drugs—side effects can be
debilitating…especially in the elderly
• Amitryptyline (Elavil)—the higher the dose, the higher the risk
of anti-cholinergic effects; dose of drug used for the
treatment for neuropathic pain vs. Rx for depression
• Doxepin (Sinequan)
• Meclizine (Antivert)
• Captopril (Capoten), nifedipine (Procardia)
• Prednisolone
• dig, dipyridamole (Persantine)
• Warfarin
• isosorbide dinitrate (Isordil)
• Hyoscyamine (Anaspaz) (from the henbane plant)*
• Atropine from the “deadly” nightshade (Atropa belladonna)*
76
“Witche’s brew”—atropine (deadly nightshade), henbane
(scopolamine— “twilight sleep”), mandrake (+/- hemlock)
• Witche’s brew (9th to 13th centuries) was a
popular analgesic and hallucinatory potion—
what was in it?
• Physician to Pope Julius III wrote that he used
Witche’s brew to anoint (from head-to-toe),
the wife of a hangman so that she could
relieve herself of nightmares related to her
husband’s job
• How was it administered?
Tincture of belladonna
• Juice from the belladonna berry was squeezed
into the eyes of Renaissance ladies to impart a
‘doe-eyed beauty’ look…women with big pupils
are more attractive
• Studies have shown that when choosing between
the two pictures of a beautiful woman--one
picture with constricted pupils and the other with
dilated pupils– the picture with dilated pupils will
always be chosen as the most beautiful of the
two
Cleopatra’s experiments
• The deadly nightshade plant has historically been
used to kill people—Cleopatra, for example, was
experimenting with ways to kill herself so she
used her slaves for acute toxicity tests
• She tried henbane and the deadly nightshade
(rapid but painful), strychnine quick but
contorted facial expression (risus sardonicus)
• Finally chose the asp’s venom for a rapid and
tranquil passage into the afterworld
And more anticholinergic drugs…
•
•
•
•
•
•
•
•
•
•
•
Paroxetine (Paxil)
Morphine, Codeine*
Oxycodone*
Diphenhydramine (Benadryl)
Fexofenadine (Allegra)
Hydroxyzine (Atarax)
Loratadine (Claritin)
dicyclomine (Bentyl)
Cimetidine (Tagamet), ranitidine (Zantac)
Haloperidol (Haldol)
*Opioids exert a tonic inhibitory effect on the micturition
reflex; consider this possibility if a patient can’t void after
surgery…
• Older patients who can’t void…check OTC drugs
80
Why the name “sympathetic”?
• The Greek physician, Galen, first detected nerve
fibers that originated from what we now know as
the autonomic nervous system
• He suggested that these nerves carried the
“sympathies,” those visceral emotional reactions
that are immortalized in such phrases as “his
heart leaped with joy” (palpitations)
• It took another 1,800 years to work out the
anatomy of the autonomic nervous system and
figure out that this wasn’t exactly the case…
Epinephrine and norepinephrine are
the neurotransmitters of the SNS
• Epinephrine – named in1898 by J. J. Abel, the
physiologist who isolated the
sympathomimetic substance from the adrenal
gland which happens to be situated above
(epi-) the kidney (Greek, nephros).
• Adrenalin (logical Latin name, from “adrenal”
gland, for the same substance), was taken
over as a trade name
The Chinese and ma huang
• Centuries ago the Chinese discovered a new
treatment for asthma—a tea made from herbs
that they called ma huang.
• Not only did it help the asthmatic breathe
(bronchodilate), they also felt refreshed and
invigorated after a hit of that tea
• If they drank too much of the tea, they became
tense, overstimulated, and experienced tremors
and palpitations
• Active ingredient? EPHEDRINE
Amphetamine
• Fast forward—In the 1920s synthetic
amphetamine was discovered to mimic the
effects of ephedrine for asthmatics—over-the
counter inhalers were called benzedrine inhalers
• Didn’t take long for people to use them as “pickme-ups” and by the 1940’s benzedrine was given
to U.S. soldiers to pep ‘em up, improve morale,
reduce sleepiness, and “increase their confidence
in their shooting ability.”
Add a methyl group to amphetamine
and the result is disastrous…
• Methamphetamine (crystal meth, ice)—the
methyl group facilitates passage into the brain
and enhances the drug’s potency
• Central site is the locus ceruleus—triggers the
release of norepinephrine (energy!) and triggers
the release of dopamine from the mesolimbic
system—reward system with euphoria, increased
mental, physical , and sexual activity and the
overwhelming desire to do the drug non-stop
• Stay tuned for more on methamphetamine in the
dopamine section…
Receptors for the sympathetic nervous
system
• Alpha-1—norepinephrine interacts with the alpha-1
receptors on the arteriole smooth muscle
(vasoconstriction to increase BP)
• On the other hand, alpha-1 blockers include the
“osins”—(prazosin /Minipress), terazosin/ Hytrin),
doxazosin/ Cardura)—used to be first line for HBP,
but they’re so potent they can make you pass out
with the first dose—first dose “syncope”
Receptors for the sympathetic nervous
system
• Interestingly, alpha-1 receptors are also
located on the smooth muscle of the prostate
gland—alpha-1 blockers are used to treat BPH;
tamsulosin (Flomax)
Receptors for the sympathetic nervous
system
• Alpha 2 (brain only)—inhibitory receptors;
clonidine (Catapres, Dixirit in Canada) inhibits
norepinephrine in the brain and SNS
outflow—calms you down and decreases
blood pressure via central mechanisms
• Norepinephrine in the brain also controls the
hypothalamic thermostat
• Can be used for hot flashes in women who
cannot, will not, take estrogen
Receptors for the sympathetic nervous
system
• B1—found on cardiac muscle and the SA
node; epinephrine binds to B1 and increases
heart rate and strength of contraction
(chronotropic and inotropic)
• Teaching tidbit—thyroid hormone modulates
the # of B1 receptors on the heart
• Too much thyroid hormone? Tachycardia
• Too little thyroid hormone? Bradycardia
Receptors for the sympathetic nervous
system
• B2—when epinephrine binds to the B2’s on
the skeletal muscles (tremors), bronchioles of
the lungs (bronchodilation), large arteries of
the legs (vasodilation)
• In other words, ya’ got the shakes, you’re
suckin’ in air as fast as you can, and your arms
and legs are ready to run
• Drugs can ‘selectively’ modulate the various
receptors
“Olols, alols, ilols”—Beta blockers
•
•
•
•
•
•
•
•
acebutolol (Sectral) {Rhotral in Canada}
atenolol (Tenormin)
betaxolol (Kerlone)
bisoprolol (Zebeta) {Monocor in Canada}*
carvedilol (Coreg) (non selective, alpha-1 blocker)*
Esmolol (Brevibloc)
labetalol (Trandate)(Normodyne)—safe during pregnancy
metoprolol succinate* and tartrate (Toprol XL, Lopressor)
{Betaloc in Canada}* (not tartrate for CHF)
• *EBM (evidence-based medicine) for heart failure to prevent
remodeling of the heart
Beta-blockers, continued…
• nadolol (Corgard)
• nebivolol (Bystolic)(also boosts the release of
nitric oxide—a potent vasodilator)
• oxprenolol (Trasicor, Slow-Trasicor)
• penbutolol (Levatol)
• pindolol {Visken—in Canada}—intrinsic
sympathomimetic activity (increases HR)
• propranolol (Inderal)(1968)
• timolol (Blocadren)
A few more notes on beta blockers…they can be
selective for B1 or non-selective and block both B1
and B2
Why don’t we pick just any old beta blocker?
Because the non-cardioselective beta blockers
block both the B1 AND B2 receptors and can
wreak havoc in certain patient populations
• B2 blockade can cause bronchoconstriction
and exacerbate COPD & asthma as well as
vasoconstrict the femoral artery {exacerbate
peripheral artery disease}
propranolol (Inderal), nadolol (Corgard),
timolol (Blocadren), carvedilol (Coreg)
One other property of beta blockers to
consider…
• Water-soluble? (low lipophilicity (not very fat-soluble)—less CNS
side effects)
• What does that mean? Beta blockers that cross the blood brain
barrier can block norepinephrine’s “energy” producing effects and
cause the Beta Blocker BLAHS…aka, anhedonia
atenolol (Tenormin), nadolol (Corgard), labetalol (Trandate), nebivolol
(Bystolic) tend to be more water soluble
• Lipid-soluble? (high lipophilicity--cross the blood brain barrier)—
CNS side effects—anhedonia (the “Blahs”)—BUT…the lipid-soluble
beta blockers can also “calm down” the “hyperenergetic “ brain
• propranolol (Inderal) is the most lipophilic of all, timolol
(Blocadren), metoprolol (Lopressor, Toprol XL), pindolol
• All of the others are moderately lipophilic
When would you use beta blockers?
• Decrease palpitations during panic attacks
• Decrease essential tremors (need a lipid soluble one
for this)
• Decrease situational anxiety(lipid-soluble one)
• Decrease symptoms of PTSD (lipid-soluble one)
• Episodic dyscontrol syndrome (lipid
• Decrease HR in patients with Grave’s disease
• Decrease portal pressure in patients with cirrhosis
and esophageal varices
The elderly patient and beta blockers
• Older adults have fewer beta receptors and those
receptors are not as likely to bind to adrenergic
particles; hence, beta adrenergic blocking and
beta-agonist medications are not as effective as
they are in younger individuals
• One reason why beta blockers are no longer
considered first line therapy for hypertension
• But we still use beta blockers in the elderly to
decrease remodeling of the heart in CHF patients,
but we use the CAREFULLY
If you can block ’em you can boost
‘em…Beta -2 agonists for asthma
• Short-acting bronchodilators boost beta-2 receptors to open
up the lungs in asthmatics
• Albuterol (Ventolin, Proventil)
• Fenoterol {Berotec}
• Levalbuterol (Xopenex, Xopenax HFA)
• Metaproterenol (Alupent)
• Terbutaline (Brethaire)
• Pirbuterol (Maxair)
• Epinephrine – beta-1 and beta-2 –used emergently—good
news is bronchodilation; bad news cardiac SE
• Isoproterenol (Isuprel)—similar to epinephrine
Beta agonists—long-acting
• Arformoterol (Brovana)(not for kids)
• Formoterol (Foradil, Perforomist){Oxeze
Turbuhaler}
• Salmeterol (Serevent Diskus)—long-acting; not
for acute bronchospasm; lasts 12 hours; has
some beta-1 boosting effects and may cause
tachycardia
• How do you know when all of your beta-2 sites
have been saturated? The patient will develop a
tremor…no more inhaler!
If you can block ‘em, you can boost
‘em…Beta-1 agonists (boosters)
• Dobutamine (Dobutrex) has a beta-1 preference—at
moderate doses it increases contractility without
increasing the heart rate—drug of choice to
stimulate the heart
• Dopamine (Inotropin)—dopamine infusions can
stimulate peripheral dopamine receptors as well as
alpha 1 and beta 1 receptors; low doses constricts
arterioles in sites other that the brain and kidney;
increased contractility
• Levophed is an alpha-1 booster to vasoconstrict in
patients with refractory shock (“left-for-dead”)
Receptor activity of cardiovascular
agents commonly used in septic shock
• Dopamine (Inotropin)
α₁ -- ++/+++
α₂ -- ?
β₁ -- ++++
β₂ -- ++
Dopaminergic -- ++++
Dopamine in doses greater than 5 mcg/kg/min is used to
support blood pressure and to increase cardiac index.
Low dose dopamine is NOT effective to increase renal
and mesenteric perfusion in shock patients
Receptor activity of cardiovascular
agents commonly used in septic shock
• Dobutamine—(Dobutrex--confusing, sounds like dopamine
but isn’t)
α₁ -- +
α₂ -- +
β₁ -- ++++
β₂ -- ++
Dopaminergic – 0
Dobutamine in doses of 2 to 20 mcg/kg/min is an alphaadrenergic inotropic agent that many clinicians prefer for
improving cardiac output and oxygen delivery. Dobutamine
should be considered in severely ill septic patients with
adequate filling pressures and blood pressure but low
cardiac index
Receptor activity of cardiovascular
agents commonly used in septic shock
• Norepinephrine
α₁ -- +++
α₂ -- +++
β₁ -- +++
β₂ -- +/++
Dopaminergic – 0
Norepinephrine is a potent α-adrenergic agent
(0.01 to 3 mcg/kg/min); useful as a vasopressor
to restore adequate blood pressure and organ
perfusion with appropriate fluid resuscitation
Receptor activity of cardiovascular
agents commonly used in septic shock
• Phenylephrine (Neo-synephrine)
α₁ -- ++/+++
α₂ -- ?
β₁ -- ?
β₂ -- 0
Dopaminergic – 0
Receptor activity of cardiovascular
agents commonly used in septic shock
• epinephrine
α₁ -- ++++
α₂ -- ++++
β₁ -- ++++
β₂ -- +++
Dopaminergic – 0
Epinephrine in doses of 0.1 to 0.5 mcg/kg/min,
increases cardiac index and produces peripheral
vasoconstriction. It is reserved for patients who
do not respond to traditional therapies
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)
• 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…cocaine, heroin, alcohol, nicotine, gambling,
methamphetamine, sex, McDonald’s French fries
• Movement—get up and get moving; control of
voluntary movements and postural reflexes
Who keeps dopamine in check? Your momma…
GABA aka gamma-amino butyric-acid
•
•
•
•
•
What’s the only word a mother needs to know?
NO, Stop, Don’t, Negative…she is inhibitory
Dopamine is like a little toddle, GABA says CALM DOWN
Your momma isn’t fully developed until your early 20’s
ETOH takes the place of GABA with chronic use
107
Alcohol addiction, GABA, and
dopamine
• 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—resulting in the DTs with s & s of catecholamine
excess
• The GABA-BZ receptor—boosting the GABA receptor with BZ’s
during alcohol withdrawal puts the brakes on dopamine
rebound
• 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)
So what else can we become addicted
to?
•
•
•
•
•
•
•
•
Methamphetamine
Cocaine
Nicotine
Morphine
Oxycontin
Heroin
Methadone
French fries
“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?
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
• Adolescents become addicted faster and with lower
doses of addictive agents including oxycontin, meth,
marijuana, alcohol, and nicotine
• Adolescents are hypersensitive to the value of
experiences, and…
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.
“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
Dopamine—too much? Too little?
• Too much can cause psychosis and hallucinations
(think schizophrenia)—lack of pruning? Lack of
apoptosis? Genes? Prenatal infection? Diet during
pregnancy?
• Too much can cause anxiety, fidgety (think cocaine
users)
• Too much is involved in addictive behaviors
• one recent finding—excess dopamine is found in
patients with anorexia nervosa—increased
reward/reinforcement
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
The older antipsychotics blocked both
D1 and D2
• 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),trifluoperazine Stelazine)—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
• Thought to improve negative symptoms, hence the term
“atypical”—but no difference between old and new w/ neg sx
• 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.)
• 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
•
•
•
•
•
•
•
Clozapine (Clozaril)(’90),
olanzapine (Zyprexa)(’96),
risperidone (Risperdal)(’93),
quetiapine (Seroquel)(’97),
ziprasidone (Geoden)(‘01),
aripiprazole (Abilify)(’02)*,
olanzapine + fluoxetine = Symbyax (approved for depressive
episodes associated with bipolar disorder);
• paliperidone ER (Invega)
• *Dopamine system stabilizer (partial agonist at D2 and 5HT1A/ full antagonist at 5-HT2A)
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
• Wt. gain
Clozapine>olanzapine>risperidone/paliperidone>que
-tiapine>ziprasidone/aripiprazole
Atypical antipsychotics
• As the risperidone/paliperidone/ziprsidone
dose increases, so do the extrapyramidal
system (EPS) side EPS effects
• But not quetiapine (Seroquel) or clozapine
(Clozaril)
DIGRESSION: What does
“extrapyramidal” mean?
• Location, location, location…the motor areas
of the brain
• There are 3 motor areas of the brain—the
corticospinal tract, the basal ganglia, and the
cerebellum
• the corticospinal tract used to be called the
pyramidal tract because it crossed to supply
the opposite side of the body in the
“pyramids” of the medulla
121
The 3 motor areas
• The corticospinal pathway/tract is the voluntary motor
pathway controlled by YOUR MOTHER (inhibitory) in
the frontal lobe—damage results in spasticity,
hyperreflexia, Babinski response
• The basal ganglia controls posture, righting reflexes,
and involuntary movements—dysfunction results in
either hyperkinesia (too much movement) or
bradykinesia (too little movement—known as
Parkinsonism when induced by a drug)
• The cerebellum controls tone, synergy, equilibrium,
and balance—hypotonicity, dysdiadokinesia,
dysmetria, wide-based gait
122
The basal ganglia
• The basal ganglia is located just “outside” the
internal capsule of the corticospinal/pyramidal
tract, hence the term, extrapyramidal
• When drugs cause “extrapyramidal effects”
patients can exhibit involuntary movements such
as dyskinesias (dystonias), tardive dyskinesia-tongue thrusting (“fly-catching”), choreaform
movements, athetoid movements, or
bradykinesia, such as Parkinson-like effects
(rigidity, lack of spontaneous movements)
123
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)
124
• 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 reconsider what is “febrile” in a patient on
neuroleptic drugs
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
•
•
•
•
Huntington’s chorea
Crack cocaine
Carbon monoxide poisoning
Tourette’s syndrome
127
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
Drugs and the cerebellum
• Booze is the best example—hypotonia,
dysarthric speech, dysmetria,
dysdiadochokinesia (difficulty making rapidalternating movements)
• Phenytoin (Dilantin)—end-positional
nystagmus
129
The “older” antipsychotic drugs
• Well known for their “extrapyramidal” effects
• Haloperidol, Thorazine, Navane,
• Risperidone can also cause extrapyramidal effects –
dose-related; the higher the dose, the greater the risk
• Did you also know that schizophrenics, in general, are
at risk for extrapyramidal symptoms, even WITHOUT
drug therapy?
• Tardive dyskinesia 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)
130
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
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
132
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 )
133
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.
134
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 disease
• By the time signs and symptoms of PD emerge,
approximately 50% of the dopaminergic neurons in the
substantia nigra have degenerated, and more than 6080% 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
• 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
A long time ago, in Asia, a legend
began…
• Buddha has cut off his eyelids in order to
prevent sleep overtaking him, and where his
eyelids fell to earth a herb grew, which
blossomed bearing a beautiful nodding violet
flower that gave sleep and tortured dreams to
mankind.
Opium poppy—Papaver somniferum
• The flower being described here is the opium
poppy, and the natural product that this plant
produces, known as opium/ or its main
constituent, morphine.
• The dichotomy of this myth, in which Buddha, a
powerful symbol of good, gives rise to a flower
that taunts mankind with disturbed sleep, is
reflected in the contrasting biological properties
of morphine. This natural product not only has
the power to alleviate intense pain, but also
rapidly induces dependence and addiction.
Let’s run through a few historical
highlights…
• 5000 B.C.—opium was used
by the Sumerians—called it
“joy” or “rejoicing”
• 2500 B.C.… evidence of
eating poppy seeds among
the Lake Dwellers on
Switzerland
• Ebers papyrus (1500 B.C.)—
opium was used as a
remedy for a colicky child
Historical highlights
• In the 2nd century AD the Greek physician
Galen prescribed opium for just about
anything that ails ya’—from asthma to
epilepsy; dropsy to leprosy and for…
• “troubles to which women are subject..”
Historical highlights
• 600s to 800s AD—opium
was introduced into Persia,
India, and the area that is
now known as Malaysia
• 1644 Emperor Tsung Chen
of China prohibited the use
of tobacco because of
health hazards and opium
was introduced as an
“alternative”
Meanwhile, back in China…
• Since they had limited
access to tobacco, the
Chinese started smoking
opium instead; by the end
of the 17th century, ¼ of the
population was using opium
• Approx. 200 years later—
1792—the first prohibitory
laws against opium
distribution in China; the
punishment decreed for
keepers of opium shops was
strangulation
And, it wasn’t just China…
• All of the Asian countries started growing their
own poppy plants after introduction into their
countries
• Opium was used primarily as a sedative and as
a treatment for diarrhea
Fast forward to today-- opiates and the
bowels…
• Morphine—a major side effect is constipation because it
stimulates the mu receptors of the bowel and reduces
gastrointestinal motility
• We also use an opiod-like drug, Lomotil , for the treatment of
diarrhea (atropine sulfate + diphenoxylate HCl)
• “Lomotil is so good, it will…”
• Loperamide (Imodium)
• Undiarrhea (Taiwan)
• Stopit (Israel)
By the way…
• Codeine isn’t that great for pain management
because of its side effects; but as the dose
escalates, so do the side effects;
• major side effect is constipation
• Actually the reason that codeine works so well
is because you are too constipated and
miserable to even feel the pain
Start a bowel program…
• Usually a combination of the senna alkaloids
and a stool softener is sufficient
• Commence with a bowel program
immediately…
Relistor
• It’s almost impossible to not get constipated from
opiods because of their effects on motility.
• Relistor (methylnaltrexone) is an opiod
antagonist. Hmmmm…if it antagonizes opiods
then how do the opiods manage the pain?
• Here’s the beauty of Relistor. Once the “methyl
group” is added to naltrexone, it prevents the
antagonist from entering the brain and blocking
the opiod effects in the brain. Relistor just blocks
the opiod effect in the bowels. Almost 50% of the
patients will find relief within just 4 hours of
taking Relistor—hallelujah! It’s an injection by the
way—subQ and it’s primarily approved for
palliative care patients that are not getting relief
from any other regimen. `
Galen also mentioned that the brain received
pain sensations…and he had the right idea…
• Fast forward to the role of the
brain today…
• The parietal lobe of the cerebral
cortex integrates and interprets
pain sensations— “that cinder
block that I just dropped elicited
an excruciating pain on the dorsum
of my left”
• Cingulate gyrus—governs the
emotional response to pain
• “!!@#**!! that HURTS”
Midbrain and mesolimbic area
• Thalamus—relay station (to and from the
periphery)—”OUCH—that’s a 10 on the pain
scale!”
• Hippocampus—learning and memory “Don’t
forget you did that, you idiot…”
• Amygdala/nucleus accumbens—treating the
excruciating pain with narcotics not only
activates the pain control system but also
activates the dopaminergic reward system
• Wow, that feels so good, let’s do it again…and
again…and again…
Head back to a laboratory in Germany…
• 1803—Friedrich Wilhelm Sertürner synthesized a substance
from crude opium—named it morphine after Morpheus (the
Greek god of dreams)
• “Wrapped in the arms of Morpheus”…
• The milky exudate from the poppy seed contains about 25
percent by weight of opium alkaloids, of which morphine (up
to 17% by weight) and codeine (up to 4% by weight) are major
constituents
• Codeine was isolated in 1832 by Pierre-Jean Robiquet
Historical highlights—from poppy seed to
the devil weed
• 1853—hypodermic syringe was
invented and morphine was
widely used for pain relief during
the American Civil War
• 1874, Alder Wright of St. Mary’s
Hospital Medical School prepared
a morphine analogue,
diacetylmorphine, which was
marketed by Bayer Company in
1898
• Hailed as a “heroic” drug—hence,
the name heroin;
• Was widely used as a cough
suppressant
Hop over Johns Hopkins to Baltimore,
MD.
• 1889—The Johns Hopkins Hospital, in
Baltimore, Maryland, opened its doors. One of
its world-famous founders, Dr. William
Stewart Halsted, was a morphine addict. He
continued to use morphine in large doses
throughout his phenomenally successful
surgical career lasting until his death in 1922.
Opiate receptors were discovered in
1972
• Discovered on October 25, 1972 by Candace Pert,
a PhD student at Johns Hopkins University
(Soloman Snyder was her mentor)
• Pert used a radioisotope-tagged opiate
antagonist, naloxone, to find opiate receptors in
the brain
• Opiate receptors were named mu, kappa, and
delta)—location in cerebral cortex, nucleus
accumbens, thalamus, hippocampus, brainstem
and spinal cord
And then?
• someone had to find the molecules produced
by the brain that interacted with the receptors
• That took a few more years and eventually 3
families of endogenous opiod-like peptides
were discovered
• Endorphins (endogenous morphines),
enkephalins (Greek for “in the head”),
dynorphins
Candace Pert and Bill Moyers—Healing and the
Mind
• The psychoneuroimmunology—mind-body
connection
• Candace Pert was being interviewed by Bill
Moyers on a PBS show and she was prattling on
about her discovery and how fascinating the
endorphins were nd that the endorphins are not
just found in the nervous system but throughout
body tissues……blah, blah, blah…and THEN…she
leaned over…and said…
• “Why Bill, you would be surprised that there are
more endorphins in your…”
So let’s talk about the opiate/opiod
receptors…mu, kappa, delta…
• The mu (μ)-opiod receptor has a high affinity for
morphine and related opiate drugs and is widely
expressed in the brain and spinal cord
• Analgesic effects in the medial thalamus,
periaqueductal gray, median raphe, and spinal cord
• Reward and positive effects in the nucleus
accumbans (dopamine release is implicated in the
reinforcing effects)
Mu receptors
• Brainstem for effects on the cardiovascular and
respiratory systems (opioid-induced respiratory
depression), coughing, nausea and vomiting
• Eyes (miosis), bowels (constipation), urinary
sphincter (retention), duodenum (nausea)
• Intrathecal or epidural morphine (and other
opioids) can release histamine from mast cells
directly and cause hives
• Morphine is the prototypical opioid and is used
as the standard of comparison for all other
opioids
Equianalgesic doses of opioid
medications (pure mu agonists)
• IM Morphine
10 mg (MS Contin, Kadian, Avinza, Roxanol, etc)
• PO Codeine
200 mg
• PO hydrocodone 40 mg
• PO hydromorphone 7.5 mg (Dilaudid, hydromorph Contin)
• PO levorphanol
4 mg
• PO meperidine
300 mg (Demerol)
• PO methadone
20 mg (Dolophine, Metadol)
• PO morphine
60 mg
• PO oxycodone
30 mg (Roxicodone, OxyContin, Endocodone)
• Fentanyl *patch
45 to 135 mg/d or oral morphine
(Advances in Pain Management. Patient Care 2004 (September); 2329)
Fentanyl—Duragesis, Actiq, Sublimaze
Kappa receptors and delta receptors
• Kappa stimulation produces analgesia, dysphoria,
psychotomimetic effects (hallucinations), miosis,
and respiratory depression
• Mixed agonist-antagonists include pentazocine
(Talwin) butorphanol (Stadol), dezocine, and
nalbuphine (Nubain)(agonists at kappa, weak
antagonists at mu)
• Delta stimulation produces analgesia without
respiratory depression
Opioids
• Classified by their action at various opioid receptors
• Full agonist—morphine, codeine, dihydrocodeine, hydrocodone,
oxycodone, propoxyphene, hydromorphone , levorphanol, fentanyl
• Partial agonist—buprenorphine (Buprenex)(only one)
• Antagonist—naloxone and naltrexone
• Mixed agonist-antagonist-- pentazocine, butorphanol, dezocine,
and nalbuphine
• Further subdivided into ultrashort, short- and long-acting
• Morphine—short-acting, requires frequent dosing to maintain
analgesia
• Methodone and levorphanol—long-acting; methodone is
traditionally used to help addicts get off heroin
Suboxone: sublingual
buprenorphine/naloxone (4:1)
• Treatment of opioid dependence
• Less abusable than methodone
• Composed of buprenorphine (Buprenex) a partial
opioid agonist, meaning that it occupies the opiate
receptors but doesn’t cause quite the same intensity of
receptor activation (or “high”) as full opiate agonists
• Naloxone – an opiate blocker
• Can’t be crushed and abused like methodone. Taken
sublingually the buprenorphine works but naloxone is
absorbed poorly; if injected however, the naloxone
“comes alive” and doesn’t allow the high
And, we’re not done yet…if you want
synergistic action add acetaminophen
• Opioid + acetaminophen is anything with the last
name “cet”
• Lorcet (hydrocodone)
• Percocet (oxycodone)
• Roxicet (oxycodone)
• Vicodin (hydrocodone)
WATCH OUT FOR THE AMOUNT OF
ACETAMINOPHEN—OVERDOSES ARE COMMON!
TELL YOUR PATIENTS…PRESCRIBE THE DRUG
WITH THE LEAST AMOUNT OF TYLENOL…
Now, we’re done…
Bibliography
• Angier N. Woman: An Intimate Geography. 1999 Anchor Books.
• FDA February 26, 2009. Metoclopramide and Tardive Dyskinesia
• Fenton WS. Prevalence of spontaneous dyskinesia in schizophrenia. J
Clin Psychiatry 2000;61(Suppl 4):10-14.
• Mann J. Murder, Magic and Medicine. 2000. Oxford University Press.
• Medical Letter. Drugs for Tobacco Dependence. September 2008.
• Nicolaou KC, Montagnon T. Molecules that Changed the World. Wiley.
• Pert, C. Molecules of Emotion.1997. Touchstone, New York, NY.
• Porter R, Madness: A brief history. 2002. Oxford University Press.
• Restak R. Receptors.. 1994. Bantam Books.
Bibliography
• Tarascon Pocket Pharmacopoeia, 2010 Deluxe
Pocket Edition.
• Trenkwalder, C, et al. The restless legs
syndrome. The Lancet Neurology 2005; 4(8).
• Waldman SA and Terzic A. Pharmacology and
Therapeutics. 2009. Saunders.
• Winkelman JW, et al. Restless Legs syndrome:
nonpharmacologica and pharmacologic
treatments. Geriatrics 2007 (October);62(10):1316.
Some new news on migraine
headaches
• Currently, more than 300 million people
worldwide
• Two-thirds of the women between the ages of 15
and 55. (before puberty more boys than girls)
• The WHO has included migraine as one of the
four most disabling chronic medical disorders—
not to mention expensive.
• Migraines cost the U.S. economy approximately
17 billion bucks a year for lost work hours,
disability payments, and health care expenses.
Historical highlights
• Historical records suggest that migraines have
been “suffered” for at least 7,000 years. Galen in
ancient Greece attributed migraines to the ascent
of vapors, or humors, from the liver to the head.
• Galen’s described “hemicrania”—a painful
disorder affecting approximately one-half of the
head—is indeed what we refer to as migraines
today: the old word “hemicrania” eventually
became “megrim” and ultimately “migraine”.
Historical highlights of Migraine
headaches
• The “humors” explanation was popular for
hundreds of years
• Vascular hypothesis took hold in the 17th century.
And lasted over 200 years; and was finally put to
rest in the late 1980s. This hypothesis stated that
migraine pain stemmed from the dilation and
stretching of brain blood vessels, leading to the
activation of pain-signaling neurons. The vascular
hypothesis also stated that the headache was
triggered by a drop in blood flow brought about
by the constriction of these same vessels.
So what’s the scoop now?
• It appears as if migraines arise from a disorder of the
brain itself—not the vascular system. And, the part of
the brain that appears to be the culprit is the brainstem
(the bulb)
• The migraine starts as a wave (cortical spreading
depression) of intense neuronal cell activity that
spreads throughout the occipital lobe (responsible for
the visual aura) in 30% of the patients
• This hyperexcitable neuronal activity requires a 300%
increase in blood flow; however, during the actual
headache, blood flow is normal or reduced
Cortical spreading depression
• The hyperexcitable phase is followed by the
inhibitory phase, during which blood flow is
either normal or decreased as the neurons are
in a state of “suspended animation”, so to
speak.
• As the cortical spread continues, patients
experience various sensory and motor
sensations depending on the area of the brain
that is affected
Dopamine and restless leg syndrome
• The first clinical description of restless leg
syndrome (RLS) is generally attributed to 17th
century British anatomist and physician, Sir
Thomas Willis, who described “so great a
Restlessness and Tossings of their Members
ensue that the diseased are no more able to
sleep than if they were in a place of the
greatest Torture.”
Restless legs syndrome
• Causes? GABHS? Mycoplasma pneumoniae infections?
• Iron depletion—iron plays a role in dopamine release
• Check the serum ferritin levels in patients with RLS (less
than 45 mcg/L—give iron supplements
• Dopaminergic abnormality
• Circadian rhythm—melatonin exerts an inhibitory effect
on central dopamine secretion—symptoms worse at
night
• Treatment—levodopa, dopamine agonists (pramipexole
(Mirapex), oxycodone, gabapentin, valproic acid,
clonidine
Pharmacotherapy
• Anti-craving meds—
• opiod antagonist, naltrexone (Revia) w/
psychosocial treatment; also, taking 50 mg 2
hours before a high-risk situation is
particularly effective in women
• glutamate antagonist (acamprosate)
• Acamprosate may almost double the
abstinence rate among recovering alcoholics
Pharmacotherapy
• Aversive therapy
• Disulfiram (Antabuse, 250-500 mg daily)
• Blocks metabolism of acetaldehyde and
causes an unpleasant flushing reaction if taken
with ETOH
Beers List
• Most of the drugs on the Beers List have unacceptable side
effects that include anti-cholinergic side effects,
hypoglycemia, bleeding problems, increased sedation,
motor dysfunction, and/or orthostatic hypotension
• For example: haloperidol (Haldol)—a first generation
antipsychotic drug that has fallen in and out of favor over
the years; it STILL works for psychosis as well as the newer
“atypical” antipsychotics including risperidone (Risperdal);
HOWEVER, the increased risk of extrapyramidal effects of
haloperidol outweighs the benefits when compared to the
new atypical antipsychotics
• P.S the use of antipsychotics in patients with dementia
provides little or no benefit but has a significant increased
risk of cardiac arrhythmias and mortality in this group
177
Supersensitivity to dopamine
• Patients may also develop an apparent sensitivity
to dopaminergic stimulation that is expressed
clinically as dyskinesia (twisting, turning
movements), and occurs when levodopa is
peaking in serum and dopamine is peaking in the
brain
• Supersensitivity to dopamine occurred even
BEFORE antipsychotic drugs were produced; in
other words, schizophrenics have a higher rate of
tardive dyskinesia even WITHOUT treatment
• Cholinesterase inhibitors are not effect shortterm treatments for agitation, however
memantine or antidepressants such as
citalopram/Celexa might be safer and more
effective alternatives for some neuropsychiatric
symptoms
• Still a limited place for antipsychotics in the
treatment of severe neuropsychiatric
manifestations, particularly aggression; however,
use as short-term tx not for prolonged
prescribing (The Lancet Neurology 2009, Jan 8)