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Alpha receptors, Beta receptors, Kappa Receptors—It’s all GR℮℮K to me…

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1 Alpha receptors, Beta receptors, Kappa Receptors—It’s all GR℮℮K to me…
Barb Bancroft, RN, MSN 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 receptors—thyroid, cortisol, estrogen, progesterone, testosterone Receptors, receptors, receptors….they’re EVERYWHERE!

4 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)

5 Let’s start with hormones…the chain of events
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

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 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

8 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.

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) Sheehan’s necrosis of the anterior pituitary gland—infarction 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). 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

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/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…

13 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

14 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

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 Mom and BZ’s…mother’s little helpers; pregabalin and fibromyalgia and symptom reduction; melatonin and breast cancer and sleep; memantine/Namenda and Alzheimer’s disease; antagonizes glutamate excitation; pit bulls and norepinephrine

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 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

17 Many receptors can be involved in body functions—Nausea and vomiting, for example

18 the duodenum of the GI tract.
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: 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 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

21 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

22 CHEMO: major cause—who makes you throw up the worst
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

23 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)

24 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 high-dose cisplatin-based chemo

25 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

26 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…

27 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)

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 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……….

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 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

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 system—the 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

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?

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 dose—much 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 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)

36 Serotonin

37 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…

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 receptors—5-HT (hydroxytryptymine)
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**

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 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

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 mouth”—dissolves 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 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

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 mother’s 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? Mom’s and babies… Nature vs. Nurture

51 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

52 SRIs (Serotonin Reuptake Inhibitors)
Paroxetine (Paxil)(1992) ++drug interactions; adrenergic 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
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)

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. 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)

57 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

58 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”

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. 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)

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

61 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

62 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

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 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

64 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?

65 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?

66 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 self-preservation…Feeding activities and 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)

67 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

68 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)

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 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.

71 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

72 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

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)(Gelnique—topical gel)(Oxytrol patch) propiverine (Prescriber’s Letter, June 2009;16(6):36

75 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)

76 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)*

77 How was it administered?
“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?

78 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

79 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

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 can’t void after surgery… Older patients who can’t void…check 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 wasn’t 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 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

84 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 “pick-me-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.”

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 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…

86 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”

87 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)

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 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

89 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

90 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

91 “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

92 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)

93 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)

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 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

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 Grave’s 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 ‘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

98 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!

99 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”)

100 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

101 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 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 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

103 Receptor activity of cardiovascular agents commonly used in septic shock
Phenylephrine (Neo-synephrine) α₁ -- ++/+++ α₂ -- ? β₁ -- ? β₂ -- 0 Dopaminergic – 0

104 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

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 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

107 Who keeps dopamine in check
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

108 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 ( 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 “addictions to food activate the brain in the same way that the brains of cocaine addicts are affected when they thnk about their next dose. The mere display of food, the researchers report in the journal NeuroImage, significantly increased metabolism in the areas associated with addiction. The findings suggest that the constant barrage of food images—from advertising to candy machines—may be contributing to the nation’s obesity epidemic. These results could explain the deleterious effects of constant exposure to food stimuli”; Methamphetamine and orgasms; 10,000 molecules of dopamine released in the “usual” orgasm; 70,000 orgasms released during Methamphetamine orgasm

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 D’s FRIES?

111 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…

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 6—thinking it was “cute”… “I’m allergic to alcohol and drugs—I 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 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

114 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

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 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

117 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

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/ 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

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)

121 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

122 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

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 temperatures—need to re-consider what is “febrile” in a patient on neuroleptic drugs

126 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)

127 Too much dopamine Huntington’s chorea Crack cocaine
Carbon monoxide poisoning Tourette’s syndrome

128 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

129 Drugs and the cerebellum
Booze is the best example—hypotonia, 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 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

132 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

133 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 )

134 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.

135 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%)

136 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 60-80% of dopamine has been lost. Treatment is to replace dopamine The clinical benefit of levodopa/carbidopa varies with the duration of chronic levodopa treatment Initially, symptom control is very good and most patients retain the benefits even if a dose is missed However, wearing off motor fluctuations can begin as early as several months after initiation of treatment

137 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

138 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.

139 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.

140 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

141 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..”

142 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”

143 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

144 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

145 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)

146 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

147 Start a bowel program… Usually a combination of the senna alkaloids and a stool softener is sufficient Commence with a bowel program immediately…

148 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. `

149 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”

150 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

151 Wow, that feels so good, let’s do it again…and again…and again…

152 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

153 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

154 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.

155 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

156 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

157 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…”

158 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)

159 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

160 Equianalgesic doses of opioid medications (pure mu agonists)
IM Morphine mg (MS Contin, Kadian, Avinza, Roxanol, etc) PO Codeine mg PO hydrocodone mg PO hydromorphone 7.5 mg (Dilaudid, hydromorph Contin) PO levorphanol mg PO meperidine mg (Demerol) PO methadone mg (Dolophine, Metadol) PO morphine mg PO oxycodone mg (Roxicodone, OxyContin, Endocodone) Fentanyl *patch to 135 mg/d or oral morphine (Advances in Pain Management. Patient Care 2004 (September); 23-29) Fentanyl—Duragesis, Actiq, Sublimaze

161 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

162 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

163 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

164 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…

165 Now, we’re done…

166 Bibliography Angier N. Woman: An Intimate Geography Anchor Books. FDA February 26, 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 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 Touchstone, New York, NY. Porter R, Madness: A brief history Oxford University Press. Restak R. Receptors Bantam Books.

167 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 Saunders. Winkelman JW, et al. Restless Legs syndrome: nonpharmacologica and pharmacologic treatments. Geriatrics 2007 (October);62(10):13-16.

168 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.

169 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”.

170 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.

171 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

172 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

173 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.”

174 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

175 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

176 Pharmacotherapy Aversive therapy
Disulfiram (Antabuse, mg daily) Blocks metabolism of acetaldehyde and causes an unpleasant flushing reaction if taken with ETOH

177 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

178 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

179 Cholinesterase inhibitors are not effect short-term 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)

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