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Alpha receptors, Beta receptors, Kappa Receptors—It’s all GReeK to me…

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Alpha receptors, Beta receptors, Kappa Receptors It s all GReeK to me Barb Bancroft, RN, MSN bbancr9271_at_aol.com August 4, 2010 Receptors, receptors, receptors – PowerPoint PPT presentation

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Title: Alpha receptors, Beta receptors, Kappa Receptors—It’s all GReeK to me…


1
Alpha receptors, Beta receptors, Kappa
ReceptorsIts all GReeK to me
  • Barb Bancroft, RN, MSN
  • bbancr9271_at_aol.com
  • August 4, 2010

2
Receptors, receptors, receptors
  • Alpha receptors (alpha one and twos)
  • Beta receptors (beta ones and twos)
  • Kappa receptors
  • Mu receptors
  • Muscarinic receptors
  • Nicotinic receptors
  • And

3
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 receptorsthyroid, cortisol, estrogen,
    progesterone, testosterone
  • Receptors, receptors, receptors.theyre
    EVERYWHERE!

4
Lets chat about neurotransmitters/hormones/recept
ors
  • 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)

5
Lets start with hormonesthe chain of events
  • Hypothalamicpituitary-end organ axis
  • HPAhypothalamic-pituitary-adrenal axis
  • HPOhypothalamic-pituitary-ovarian-axis
  • HPThypothalamic-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

6
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

7
Pituitary gland
  • Pituitary comes from the Latin pituita, meaning
    phelgm,, also related to the Greek ptuo,
    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

8
But you actually have two separate pituitary
glandsthe 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
    originsectoderm for the posterior and endoderm
    for the anterior.

9
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)
  • Sheehans necrosis of the anterior pituitary
    glandinfarction of the anterior pituitary during
    delivery (sudden loss of blood via hemorrhaging)

10
Oxytocin
  • The first peptide ever to be replicated outside
    the body was oxytocin (1953). Its 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

11
Women and oxytocin
  • Tend and befriend
  • Cuddly, momma-earth hormone
  • Milk let-down response
  • Uterine contractions during orgasm
  • Hormone of monogamy
  • Men and oxytocin? HELLO???

12
The hierarchy of messaging in the endocrine system
  • Gonadotropin-releasing hormone/factorGn-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 organone 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?

13
Whoa, not so fast
  • Inhibiting factors can also be released a real
    important one is PRL-IFof 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 receptorsmore
    later)
  • A common tumor of the pituitary gland is a
    prolactinoma and of course, one of the symptoms
    is un-called for galactorrhea

14
And then there are mega-molecules released from
the hypothalamus/pituitary
  • Proopiomelanocortin
  • Gotta little bit of everything in it
  • Opio enkephalins (in the headendogenous
    opiates)
  • Melanomelanocyte stimulating hormone
  • Cortincorticotropin releasing factor

15
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

16
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 its
    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

17
Many receptors can be involved in body
functionsNausea and vomiting, for example
18
Many receptors can be involved in body
functionsNausea and vomiting, for example
  • Numerous receptors are located in 3 major areas
    (central and peripheral ) for nausea and
    vomiting
  • the vomiting center of the brainstem (known as
    the TVC, or true vomiting center where all
    vomiting eventually goes through), and
  • 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
  • the duodenum of the GI tract.

19
What receptors?
  • Cholinergic
  • Histaminergic
  • Dopaminergic
  • Opiate receptors
  • Benzodiazepine receptors
  • Serotonin receptors
  • Substance P
  • Cannaboid receptors

20
Lots of etiologies
  • GI disturbancesobstructions, gastroparesis, PUD,
    pancreatitis, pyelonephritis, cholecystitis,
    cholangitis, hepatitis, acute gastroenteritis
    (viral, bacterial)
  • Neuroincreased ICP, migraine headache,
    vestibular disorder
  • Metabolicketoacidosis, Addisons disease, uremia
  • Psych causespsychogenic, anxiety, anorexia,
    bulimia
  • CV diseasesMI (inferior/diaphragmatic/right
    ventricle) CHF, radiofrequency ablation

21
Lots of etiologies
  • Therapy-induced causescytotoxic chemotherapy,
    radiation therapy, theophylline preparations,
    anticonvulsant preparations, digitalis
    preparations, opiates, antibiotics, anesthetics
  • Drug withdrawalopiates, benzodiazepines
  • Miscellaneous causespregnancy, noxious odors

22
CHEMO major causewho 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, streptozotocinANTI
    CIPATORY N V
  • Moderate risk (30 to 90)carboplatin, cytarabine
    gt 1 g/m², daunorubicin, doxorubicin, epirubicin,
    idarubicin, ifosfamide, irinotecan, oxaliplatin

23
Emetogenicity of chemotherapeutic agents
  • Low risk (10 to 30)bortezomib, cetuximab,
    cytarabine lt 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)

24
So who blocks what?
  • Histamine 2 antagoniststhe 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
    antagonistsaprepitant / Emend--is the first
    approved member of this class of drugs part of a
    multiple drug regimen for N and V associated with
    high-dose cisplatin-based chemo

25
So, who blocks what?
  • Antihistaminic-anticholinergiccyclizine
    (Marezine), dimenhydrinate (Dramamine),
    diphenhydramine (Benadryl), hydroxyzine
    (Vistaril, Atarax), medlizine (Bonine, Antivert),
    scopolamine (Transderm Scop), trimethobenzamide
    (Tigan)
  • Used for simple N and V (motion sickness, inner
    ear problems)adverse reactions can be miserable
    tho--in the elderlya mouth like the Mohave
    desert, confusion, blurred vision, urinary
    retention, and possibly tachycardia

26
So, who blocks what?
  • Serotonin (5-HT3) antagonistsdolasetron/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
    sayas Im not the one with N and V from
    cisplatin)but as an old Peds Onc Nurse

27
So, who blocks what?
  • Phenothiazines -- chlopromazine(Thorazine),
    prochlorperazine (Compazine), promethazine
    (Phenergan), thiethylperazine (Torecan)
  • Cannabinoidsdronabinol (Marinol), nabilone
    (Cesamet) chemo for cancer
  • Butyrophenoneshaloperidol (Haldol), droperidol
    (Inapsine)
  • Benzodiazepines alprazolam (Xanax), lorazepam
    (Ativan)
  • Dopamine blockermetoclopramide (Reglan)(more
    later on side effects)

28
Name that transmitter
  • 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 reportthe 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.

29
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 efficiencypossible clinical use
    in AD in the future as a transdermal skin patch
    (smokers actually have less Alzheimers)
  • Tourettes syndrome, ulcerative colitis

30
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 systemthe cigarette delivers
    the hit of nicotine to the brain in 7 seconds

31
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

32
IS THIS A HEALTH PROBLEM?
  • The first manufactured cigarette appeared in the
    U.S. in the 1860s and by 1884, James B. Duke was
    producing almost a BILLION cigarettes per year
  • P.S. DUKE University is researching the medical
    benefits of nicotinerather ironic, eh?

33
How do you stop smoking?
  • Willpower? Cold turkey?
  • Easier said than done
  • Usually takes 5 or 6 attempts

34
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 dosemuch LESS than a pack of cigs

35
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 eventsagitation, hostility,
    depression, suicidal ideation, suicidal behavior
  • 98 suicides on Chantix 14 on Zyban
  • Dont discourage use encourage monitoring and
    specific questions about suicide, esp. in
    patients with pre-existing psych disorders
    (Tonstad)

36
Serotonin
37
More historical highlights
  • 1958Serotonins ability to contract a rats
    uterus was found to be antagonized by LSD
  • And, the question begs to be asked Who gives
    al rats
  • The bigger question needs to be askedwhy were
    they using LSD in a rats uterus?
  • LSDs schizophrenic-like effects (serotonin and
    dopamine excess) were discovered shortly
    thereafter

38
Serotonin (a.k.a. 5-HT, or 5-hydroxytryptamine)
  • 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

39
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

40
Serotonin receptors5-HT (hydroxytryptymine)
  • 5-HT1, 5-HT2, 5-HT3, 5-HT4
  • Subtypes5HT1A, 1B, 1C, 1D, 5-HT2A, 2B
  • Get it?
  • 5-HT1Aif you boost it you will be anxious if
    you block it you will reduce anxietyBuspirone
    (Buspar) blocks this receptor
  • 5-HT2Cblocking this receptor results in
    increased food intake and weight gain
    antipsychotics such as olanzepine (Zyprexa),
    clozapine (Clozaril) interestingly so does the
    oldest antipsychoticThorazine
  • 5-HT1B/1Dif you boost it vasoconstriction will
    occur the triptans are 5-HT1D
    agonists/boosters given during the acute phase of
    migraine headaches

41
So where does the pain come from?
  • Two theories
  • Pain is caused by the cortical spreading
    depression that triggers the brainstem and
    trigeminal nucleus pain pathways
  • Pain may originate in the brainstem centers for
    painthe nucleus raphe, the locus coeruleus, and
    the periaqueductal gray matter these three
    centers are responsible for controlling the flow
    of sensory informationlight, noise, smell,
    painthat reaches the cortex

42
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

43
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

44
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 mouthdissolves on tongue no
    need for water

45
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 diseasecontraindicated in CAD
  • However, common triptan side effects include
    tightness, heaviness, pressure or pain in the
    chest, neck and throatthese are not associated
    with ECG changes and are not caused by coronary
    vasoconstriction in the majority of patients

46
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.)

47
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

48
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

49
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 mothers mouth.
    ---Tina Fey, on Saturday Night Live (March 2006)

50
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?
  • Moms and babies
  • Nature vs. Nurture

51
The SRIs (serotonin reuptake inhibitors)
  • 1987the 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

52
SRIs (Serotonin Reuptake Inhibitors)
  • Paroxetine (Paxil)(1992) drug interactions
    adrenergic effectstremor14.7 _at_ 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

53
Give antidepressants time to work! 3-5 weeksbut
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
    SRIsin some cases by the end of week one)

54
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?

55
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

56
Implications for low-carb diets
  • Dr. Atkins, Dr. Agatston (South Beach)
  • Is she really that happy? NOOOOOOOOO
  • Females without carbsno energy, depressed,
    constipated with halitosis
  • Men love their red meat why? (meat contains
    tyramine, the precursor to the catecholamines)

57
Weight loss drugs
  • The weight loss drugs target the satiety center
    in the hypothalamusboost serotonin that tells
    you stop eating, youre full
  • Redux and Fenphen increased serotonin in the
    satiety center
  • Meridia (sirbutamine)prevents the re-uptake of
    serotonin in the satiety centerweak
  • NEW and excitinglorcaserin, a selective
    seratonin 5-HT2C agonist, is in phase III
    clinical trialshelps to lose weight and MAINTAIN
    weight losscoming to a prescribers pad near you
    shortly
  • NO increased risk for valvular heart disease like
    fenphen

58
Chocolate also boosts serotonin
  • In addition to increasing serotonin in the brain,
    chocolates trigger anandamidethe only natural
    marijuana receptor-stimulating chemical
    discovered at this point
  • ananda in Sanskrit means bliss
  • Bliss is a 1 lb bag of M Ms
  • Marijuana and the munchies

59
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. Johns 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)

60
St. Johns Wort
  • St. Johns 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

61
Digression St. Johns 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 depressionINTERESTING
    EFFECT as its the ONLY drug that has shown to
    reduce cortisols effects in the braindecrease
    stress? IMPROVE DEPRESSION AND MEMORY
  • ??Effective for mild depressionnot moderate to
    severe Do NOT use with other anti-depressantsesp
    ecially SSRIs

62
A few notes on medical marijuanadronabinol
(Marinol) and nabilone (Cesamet)
  • Stimulate the feeding centers in the brainused
    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

63
The autonomic nervous system
  • What is this nervous system for?
  • The preservation of the species and
    self-preservation activities
  • It automatically does this without you thinking
    about it
  • You run when youre scared, you eat when your
    hungry, you have sex because your NETflix movie
    didnt arrive in the mail and theres nothing to
    watch on TV, you reproduce so that your children
    can support you when youre old

64
Functions of the autonomic nervous system? The 4
Fs
  • Sympathetic Nervous System (SNS)nerves originate
    from the thoracolumbar areas of the spinal cord
  • fight-flight systemself-preservation when in
    danger
  • Lets say you decide to visit Chicago at 3 a.m.
    and you take a wrong-turnwhats gonna happen
    to you?

65
Fight-Flightadrenalin 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?

66
Functions of the autonomic nervous systemthe 4
Fs
  • The parasympathetic Nervous System is the
    vegetative systemday to day activities for
    preservation of the species and
    self-preservationFeeding activities and
    F_at_!king. activities.. (erection, but not the
    grand finale, ejaculation ejaculation is a
    sympathetic phenomenon)
  • Parasympatheticnerves originate from the
    craniosacral areas of the brainstem and spinal
    cord (cranial specific cranial nerves)

67
Just rememberthe 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 confusingmore later

68
Parasympathetic Nervous System (PNS)craniosacral
output--acetylcholine
  • lacrimal glandtear secretion (CNVII)
  • circular muscle of the irisconstriction of
    the pupil (CN III)
  • ciliary muscleaccommodation for near vision
    (CNIII)
  • Salivary glandssecretion of watery saliva (CN
    VII and IX)
  • heartrate and force reducedslows heart rate
    (CN X)
  • lung airwaysbronchoconstriction 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)

69
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.

70
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 horses 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 spotsa
    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.

71
Drugs can either BOOST acetylcholine receptor or
block acetylcholine receptors
  • Lets say you have a problem with urinary
    retentioncan we give you something to relax the
    smooth muscle sphincter? Absolutely, it acts just
    like acetylcholine and its name should receive
    the NOBEL prize
  • DUVOID aka, Urecholine--bethanechol is the
    generic name, and in Canada the brand name is
    Myotonachol

72
The complex mechanism of voiding
  • Its not as simple as you thinkvoiding 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

73
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

74
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)(Gelniquetopical
    gel)(Oxytrol patch)
  • propiverine
  • (Prescribers Letter, June 200916(6)36

75
Anti-cholinergic drugsside 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)

76
Anti-cholinergic drugsside effects can be
debilitatingespecially 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)

77
Witches brewatropine (deadly nightshade),
henbane (scopolamine twilight sleep), mandrake
(/- hemlock)
  • Witches brew (9th to 13th centuries) was a
    popular analgesic and hallucinatory potionwhat
    was in it?
  • Physician to Pope Julius III wrote that he used
    Witches brew to anoint (from head-to-toe), the
    wife of a hangman so that she could relieve
    herself of nightmares related to her husbands
    job
  • How was it administered?

78
Tincture of belladonna
  • Juice from the belladonna berry was squeezed into
    the eyes of Renaissance ladies to impart a
    doe-eyed beauty lookwomen 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

79
Cleopatras experiments
  • The deadly nightshade plant has historically been
    used to kill peopleCleopatra, 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 asps venom for a rapid and
    tranquil passage into the afterworld

80
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 cant void after surgery
  • Older patients who cant voidcheck OTC drugs

81
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 wasnt exactly the case

82
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

83
The Chinese and ma huang
  • Centuries ago the Chinese discovered a new
    treatment for asthmaa 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

84
Amphetamine
  • Fast forwardIn the 1920s synthetic amphetamine
    was discovered to mimic the effects of ephedrine
    for asthmaticsover-the counter inhalers were
    called benzedrine inhalers
  • Didnt take long for people to use them as
    pick-me-ups and by the 1940s benzedrine was
    given to U.S. soldiers to pep em up, improve
    morale, reduce sleepiness, and increase their
    confidence in their shooting ability.

85
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 drugs potency
  • Central site is the locus ceruleustriggers the
    release of norepinephrine (energy!) and triggers
    the release of dopamine from the mesolimbic
    systemreward 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

86
Receptors for the sympathetic nervous system
  • Alpha-1norepinephrine 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 theyre so potent they can make
    you pass out with the first dosefirst dose
    syncope

87
Receptors for the sympathetic nervous system
  • Interestingly, alpha-1 receptors are also located
    on the smooth muscle of the prostate
    glandalpha-1 blockers are used to treat BPH
    tamsulosin (Flomax)

88
Receptors for the sympathetic nervous system
  • Alpha 2 (brain only)inhibitory receptors
    clonidine (Catapres, Dixirit in Canada) inhibits
    norepinephrine in the brain and SNS outflowcalms
    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

89
Receptors for the sympathetic nervous system
  • B1found on cardiac muscle and the SA node
    epinephrine binds to B1 and increases heart rate
    and strength of contraction (chronotropic and
    inotropic)
  • Teaching tidbitthyroid hormone modulates the
    of B1 receptors on the heart
  • Too much thyroid hormone? Tachycardia
  • Too little thyroid hormone? Bradycardia

90
Receptors for the sympathetic nervous system
  • B2when epinephrine binds to the B2s on the
    skeletal muscles (tremors), bronchioles of the
    lungs (bronchodilation), large arteries of the
    legs (vasodilation)
  • In other words, ya got the shakes, youre
    suckin in air as fast as you can, and your arms
    and legs are ready to run
  • Drugs can selectively modulate the various
    receptors

91
Olols, alols, ilolsBeta 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

92
Beta-blockers, continued
  • nadolol (Corgard)
  • nebivolol (Bystolic)(also boosts the release of
    nitric oxidea potent vasodilator)
  • oxprenolol (Trasicor, Slow-Trasicor)
  • penbutolol (Levatol)
  • pindolol Viskenin Canadaintrinsic
    sympathomimetic activity (increases HR)
  • propranolol (Inderal)(1968)
  • timolol (Blocadren)

93
A few more notes on beta blockersthey can be
selective for B1 or non-selective and block both
B1 and B2
  • Why dont 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)

94
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 norepinephrines
    energy producing effects and cause the Beta
    Blocker BLAHSaka, 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 effectsanhedonia
    (the Blahs)BUTthe 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

95
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 Graves disease
  • Decrease portal pressure in patients with
    cirrhosis and esophageal varices

96
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

97
If you can block em you can boost emBeta -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
    emergentlygood news is bronchodilation bad news
    cardiac SE
  • Isoproterenol (Isuprel)similar to epinephrine

98
Beta agonistslong-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
    tremorno more inhaler!

99
If you can block em, you can boost emBeta-1
agonists (boosters)
  • Dobutamine (Dobutrex) has a beta-1 preferenceat
    moderate doses it increases contractility without
    increasing the heart ratedrug 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)

100
Receptor activity of cardiovascular agents
commonly used in septic shock
  • Dopamine (Inotropin)
  • a1 -- /
  • a2 -- ?
  • ß1 --
  • ß2 --
  • 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

101
Receptor activity of cardiovascular agents
commonly used in septic shock
  • Dobutamine(Dobutrex--confusing, sounds like
    dopamine but isnt)
  • a1 --
  • a2 --
  • ß1 --
  • ß2 --
  • Dopaminergic 0
  • Dobutamine in doses of 2 to 20 mcg/kg/min is an
    alpha-adrenergic 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

102
Receptor activity of cardiovascular agents
commonly used in septic shock
  • Norepinephrine
  • a1 --
  • a2 --
  • ß1 --
  • ß2 -- /
  • Dopaminergic 0
  • Norepinephrine is a potent a-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

103
Receptor activity of cardiovascular agents
commonly used in septic shock
  • Phenylephrine (Neo-synephrine)
  • a1 -- /
  • a2 -- ?
  • ß1 -- ?
  • ß2 -- 0
  • Dopaminergic 0

104
Receptor activity of cardiovascular agents
commonly used in septic shock
  • epinephrine
  • a1 --
  • a2 --
  • ß1 --
  • ß2 --
  • 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

105
Dopamine
106
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 wordswowWEEE!
    That felt good, lets do it again, and again, and
    againcocaine, heroin, alcohol, nicotine,
    gambling, methamphetamine, sex, McDonalds French
    fries
  • Movementget up and get moving control of
    voluntary movements and postural reflexes

107
Who keeps dopamine in check? Your momma GABA aka
gamma-amino butyric-acid
  • Whats the only word a mother needs to know?
  • NO, Stop, Dont, Negativeshe is inhibitory
  • Dopamine is like a little toddle, GABA says CALM
    DOWN
  • Your momma isnt fully developed until your early
    20s
  • ETOH takes the place of GABA with chronic use

108
Alcohol addiction, GABA, and dopamine
  • GABA (Mom) inhibits dopamine (toddlerenergy)
  • 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 reboundresulting in the DTs
    with s s of catecholamine excess
  • The GABA-BZ receptorboosting the GABA receptor
    with BZs during alcohol withdrawal puts the
    brakes on dopamine rebound
  • RX Mothers 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)

109
So what else can we become addicted to?
  • Methamphetamine
  • Cocaine
  • Nicotine
  • Morphine
  • Oxycontin
  • Heroin
  • Methadone
  • French fries

110
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 Ds FRIES?

111
Digression The Teenage Brain
  • Dopamine system of rewards is developing during
    adolescence
  • Dopamine is responsible for the highwow, this
    feels goodlets 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

112
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 6thinking it was cute
  • Im allergic to alcohol and drugsI break out in
    handcuffs. Robert Downey, Jr.

113
Well, I started cause I heard that crystal meth
was great for sex How great might that be?
  • Well, harken back to your last orgasmhmmmm
  • 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 againand again
  • The addiction potential is enormousonly 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

114
Dopaminetoo 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 findingexcess dopamine is found in
    patients with anorexia nervosaincreased
    reward/reinforcement

115
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

116
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 effectsParkinsonism, 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

117
The newer atypical antipsychotics
  • Thought to improve negative symptoms, hence the
    term atypicalbut 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 usedthese drugs just help to
    unmask it

118
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 5-HT1A/ full antagonist at 5-HT2A)

119
Atypical antipsychotics
  • Weight gain Clozapine (Clozaril)(biggest
    offender) and 2 is Olanzapine (Zyprexa) 10
    weeks/10 pounds
  • Agranulocytosis w/ Clozapine1st 3 months
    1/10,000
  • Risperidone w/ intermediate wt gain, ziprasidone
    (Geodon) with least
  • Wt. gain Clozapinegtolanzapinegtrisperidone/paliperi
    donegtque-tiapinegtziprasidone/aripiprazole

120
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)

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DIGRESSION What does extrapyramidal mean?
  • Location, location, locationthe motor areas of
    the brain
  • There are 3 motor areas of the brainthe
    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

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The 3 motor areas
  • The corticospinal pathway/tract is the voluntary
    motor pathway controlled by YOUR MOTHER
    (inhibitory) in the frontal lobedamage results
    in spasticity, hyperreflexia, Babinski response
  • The basal ganglia controls posture, righting
    reflexes, and involuntary movementsdysfunction
    results in either hyperkinesia (too much
    movement) or bradykinesia (too little
    movementknown as Parkinsonism when induced by a
    drug)
  • The cerebellum controls tone, synergy,
    equilibrium, and balancehypotonicity,
    dysdiadokinesia, dysmetria, wide-based gait

123
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)

124
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)

125
  • 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 temperaturesneed to re-consider what
    is febrile in a patient on neuroleptic drugs

126
Dopaminetoo much? Too little?
  • Too little can cause depression (chronic
    alcoholism)
  • Too little can cause too little movement (think
    Parkinsons disease or parkinsonism from
    drugslike metoclopramide/Reglan)
  • Too much can cause too much movementchorea/atheto
    sis (Huntingtons chorea)(Tourettes
    syndrome)(Tardive dyskinesia)

127
Too much dopamine
  • Huntingtons chorea
  • Crack cocaine
  • Carbon monoxide poisoning
  • Tourettes syndrome

128
Dopamine and the GI tract
  • Dopamine inhibits GI peristalsis
  • Acetylcholine boosts GI peristalsis
  • Balance between the two is 5050
  • 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

129
Drugs and the cerebellum
  • Booze is the best examplehypotonia, dysarthric
    speech, dysmetria, dysdiadochokinesia (difficulty
    making rapid-alternating movements)
  • Phenytoin (Dilantin)end-positional nystagmus

130
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)

131
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
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