1 / 179

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

Receptors, receptors, receptors

rosalba
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. Alpha receptors, Beta receptors, Kappa ReceptorsIts all GReeK to me Barb Bancroft, RN, MSN bbancr9271@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/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. 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 Mom and BZsmothers little helpers; pregabalin and fibromyalgia and symptom reduction; melatonin and breast cancer and sleep; memantine/Namenda and Alzheimers disease; antagonizes glutamate excitation; pit bulls and norepinephrine Mom and BZsmothers little helpers; pregabalin and fibromyalgia and symptom reduction; melatonin and breast cancer and sleep; memantine/Namenda and Alzheimers 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 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/m, dacarbazine, dactinomycin, mechlorethamine, streptozotocinANTICIPATORY N & V Moderate risk (30 to 90%)carboplatin, cytarabine > 1 g/m, daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin

    23. Emetogenicity of chemotherapeutic agents Low risk (10 to 30%)bortezomib, cetuximab, cytarabine < 1 gm/m, 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. 28

    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? 32

    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 t) Sertraline (Zoloft)(1992)shortest t; 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 effects=tremor14.7% @ 40 mg/d); most anticholinergic Citalopram (Celexa)(2000)most selective affinity for HT receptors; useful for mild irritablity and aggression Escitalopram(2002)(as above) (Lexapro)(#12 of the top selling drugs in 2009)**fewest SE of all SRIs

    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-depressantsespecially 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@!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 73

    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 2009;16(6):36 74

    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) 75

    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)* 76

    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 80

    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 Canada}intrinsic 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 -- ? 1 -- ++++ 2 -- ++ 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 -- + 1 -- ++++ 2 -- ++ 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 -- +++ 1 -- +++ 2 -- +/++ 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 -- ? 1 -- ? 2 -- 0 Dopaminergic 0

    104. Receptor activity of cardiovascular agents commonly used in septic shock epinephrine a1 -- ++++ a2 -- ++++ 1 -- ++++ 2 -- +++ 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 107

    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 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 imagesfrom advertising to candy machinesmay be contributing to the nations 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 orgasmaddictions 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 imagesfrom advertising to candy machinesmay be contributing to the nations 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 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 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, 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 121

    122. 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 122

    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) 123

    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) 124

    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/athetosis (Huntingtons chorea)(Tourettes syndrome)(Tardive dyskinesia)

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

    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 examplehypotonia, dysarthric speech, dysmetria, dysdiadochokinesia (difficulty making rapid-alternating movements) Phenytoin (Dilantin)end-positional nystagmus 129

    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) 130

    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 132

    133. The BASAL GANGLIA Control of movement, initiation and cessation of movement Postural reflexesthe righting reflex Dopamine levels decrease with aging graduallywe all slow down Dopamine reserves, in particular, decrease with advancing age, and medications that may affect dopamine pathways are likely to trigger extrapyramidal effects (Timiras ) 133

    134. Clinical symptoms Anosmia (loss of smell)(may predate Parkinsons disease by a decade) As can REM sleep behavior disorderin which dreams are accompanied by excessive movement (portends neurodegenerative disorders including Parkinsons disease, Lewy body dementia, or multiple system atrophy--that manifest up to 25 years later) (Boeve B, Neurology , August 10, 2010. 134

    135. Parkinsons 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. Parkinsons 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 agonistsnot 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 poppyPapaver 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. Lets run through a few historical highlights 5000 B.C.opium was used by the Sumerianscalled 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 yafrom asthma to epilepsy; dropsy to leprosy and for troubles to which women are subject..

    142. Historical highlights 600s to 800s ADopium 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, of the population was using opium Approx. 200 years later1792the first prohibitory laws against opium distribution in China; the punishment decreed for keepers of opium shops was strangulation

    144. And, it wasnt 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 Morphinea 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 isnt 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 Its almost impossible to not get constipated from opiods because of their effects on motility. Relistor (methylnaltrexone) is an opiod antagonist. Hmmmmif it antagonizes opiods then how do the opiods manage the pain? Heres 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 Relistorhallelujah! Its an injection by the waysubQ and its primarily approved for palliative care patients that are not getting relief from any other regimen. `

    149. Galen also mentioned that the brain received pain sensationsand 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 gyrusgoverns the emotional response to pain !!@#**!! that HURTS

    150. Midbrain and mesolimbic area Thalamusrelay station (to and from the periphery)OUCHthats a 10 on the pain scale! Hippocampuslearning and memory Dont forget you did that, you idiot Amygdala/nucleus accumbenstreating 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, lets do it againand againand again

    152. Head back to a laboratory in Germany 1803Friedrich Wilhelm Sertrner synthesized a substance from crude opiumnamed 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 highlightsfrom poppy seed to the devil weed 1853hypodermic syringe was invented and morphine was widely used for pain relief during the American Civil War 1874, Alder Wright of St. Marys Hospital Medical School prepared a morphine analogue, diacetylmorphine, which was marketed by Bayer Company in 1898 Hailed as a heroic drughence, the name heroin; Was widely used as a cough suppressant

    154. Hop over Johns Hopkins to Baltimore, MD. 1889The 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 MoyersHealing and the Mind The psychoneuroimmunologymind-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 tissuesblah, blah, blahand THENshe leaned overand said Why Bill, you would be surprised that there are more endorphins in your

    158. So lets talk about the opiate/opiod receptorsmu, kappa, delta The mu ()-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 10 mg (MS Contin, Kadian, Avinza, Roxanol, etc) PO Codeine 200 mg PO hydrocodone 40 mg PO hydromorphone 7.5 mg (Dilaudid, hydromorph Contin) PO levorphanol 4 mg PO meperidine 300 mg (Demerol) PO methadone 20 mg (Dolophine, Metadol) PO morphine 60 mg PO oxycodone 30 mg (Roxicodone, OxyContin, Endocodone) Fentanyl *patch 45 to 135 mg/d or oral morphine (Advances in Pain Management. Patient Care 2004 (September); 23-29) FentanylDuragesis, 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 agonistmorphine, codeine, dihydrocodeine, hydrocodone, oxycodone, propoxyphene, hydromorphone , levorphanol, fentanyl Partial agonistbuprenorphine (Buprenex)(only one) Antagonistnaloxone and naltrexone Mixed agonist-antagonist-- pentazocine, butorphanol, dezocine, and nalbuphine Further subdivided into ultrashort, short- and long-acting Morphineshort-acting, requires frequent dosing to maintain analgesia Methodone and levorphanollong-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 doesnt cause quite the same intensity of receptor activation (or high) as full opiate agonists Naloxone an opiate blocker Cant be crushed and abused like methodone. Taken sublingually the buprenorphine works but naloxone is absorbed poorly; if injected however, the naloxone comes alive and doesnt allow the high

    164. And, were not done yetif 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 ACETAMINOPHENOVERDOSES ARE COMMON! TELL YOUR PATIENTSPRESCRIBE THE DRUG WITH THE LEAST AMOUNT OF TYLENOL

    165. Now, were done

    166. Bibliography Angier N. Woman: An Intimate Geography. 1999 Anchor Books. FDA February 26, 2009. Metoclopramide and Tardive Dyskinesia Fenton WS. Prevalence of spontaneous dyskinesia in schizophrenia. J Clin Psychiatry 2000;61(Suppl 4):10-14. Mann J. Murder, Magic and Medicine. 2000. Oxford University Press. Medical Letter. Drugs for Tobacco Dependence. September 2008. Nicolaou KC, Montagnon T. Molecules that Changed the World. Wiley. Pert, C. Molecules of Emotion.1997. Touchstone, New York, NY. Porter R, Madness: A brief history. 2002. Oxford University Press. Restak R. Receptors.. 1994. Bantam Books.

    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. 2009. 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 disordersnot 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. Galens described hemicraniaa painful disorder affecting approximately one-half of the headis 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 whats the scoop now? It appears as if migraines arise from a disorder of the brain itselfnot 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 depletioniron plays a role in dopamine release Check the serum ferritin levels in patients with RLS (less than 45 mcg/Lgive iron supplements Dopaminergic abnormality Circadian rhythmmelatonin exerts an inhibitory effect on central dopamine secretionsymptoms worse at night Treatmentlevodopa, 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, 250-500 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 177

    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)

More Related