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Neurotransmitters in Health and Disease

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Neurotransmitters in Health and Disease Neurotransmitters in Health and Disease Barb Bancroft, RN, MSN, PNP CPP Associates, Inc www.barbbancroft.com [email protected] Neurotransmitters in health and disease • General theory is that many neurological disorders may be due to: ….. a deficiency of a transmitter, ….. an excess of a neurotransmitter, or ….. an imbalance between neurotransmitters • Neurotransmitters are located in all three nervous systems: the Central Nervous System (CNS), the Peripheral Nervous System (PNS), and the Enteric Nervous System (ENS, or GI tract) • One neurotransmitter is also located in platelets (serotonin)‐‐‐‐the name, serotonin, was derived from it’s ability to constrict the blood vessels (sero=serum, tonin=tonic/tone)(1948); actually the Italians first found it in the ENS and named it enteramine (1933) NEUROTRANSMITTERS—the list I’ll be touching on today • Indolamines …Serotonin (5‐hydroxytryptamine, or 5‐HT)—the most ubiquitous of all neurotransmitters; CNS (~3%), Enteric Nervous System (~92‐95%), blood platelets (~2%)—numerous functions—makes you happy, boosts self esteem, bolsters confidence (“the confidence” molecule), controls aggressive/impulsive behaviors; too much? Anxiety; nausea, vomiting …Melatonin—CNS (pineal gland) – sleep/wake cycle of our biological clock; (infants produce the most serotonin vs. elderly produce the least)—the pineal gland shrinks in size with aging and melatonin levels plummet; sundowning may be caused by a disrupted “clock”… try melatonin in patients with sundowning—try 3 mg in the late afternoon (Lammer) 1 NEUROTRANSMITTERS—the list I’ll be touching on today • Acetylcholine—located in all 3 nervous systems • In the CNS –cognitive function—mentation (90% depleted in late Alzheimer’s disease) • In the PNS (via the vagus nerve (X) primarily) –neuromuscular transmission, slows the heart down, bronchoconstriction, constricts the pupils, stimulates salivation, loosens the bladder sphincter • In the ENS (enteric) –triggers peristalsis in the GI tract (excitatory), tightens the lower esophageal sphincter NEUROTRANSMITTERS‐‐ the list I’ll be touching on today • Catecholamines—in all 3 nervous systems: CNS, PNS, and ENS Dopamine (DA)—numerous functions including the reward system (oooohhh that feels good—let’s do it again…and again), movement in the basal ganglia/striatum, vomiting in the TVC, sex drive; inhibitory in the GI tract—LES and peristalsis; Epinephrine (E)—fight/flight response Norepinephrine (NE)—energy in the CNS, appetite in the hypothalamus, aggression in the limbic system, alert NEUROTRANSMITTERS—the list I’ll be touching on today • GABA (gamma‐amino‐butyric acid)”your “mother”— inhibitory in the prefrontal cortex; calms you down; plays a major role in keeping dopamine in check in the basal ganglia • Glutamate— excitatory transmitter; excess glutamate triggers neuronal hyperexcitability (seizures); glutamate also triggers brain‐ derived growth factor and boosts neuronal connections 2 NEUROTRANSMITTERS • So we’ll be talking about everything from depression to dementia, self‐esteem to sleep disorders, sex to seizures, anxiety to addiction, marijuana to movement disorders, and irritable people to irritable bowels… • All of the above are associated with either an excess, a deficiency or an imbalance of various neurotransmitters in the three nervous systems Chuckle. • The statistics on mental disorders is that one out of every four persons are suffering from some form of mental illness. • Think of your three best friends –if they’re ok then it’s you. Receptors for neurotransmitters—back to Pharmacology 101 • In order for any neurotransmitter to do it’s job, it has to have a specific receptor (s) to interact with • Does the transmitter BOOST that receptor? If so, it will generally boost the function and action of that transmitter • Does the transmitter block that receptor? If so, it will usually block the function of the neurotransmitter • Drugs influence transmitters and receptors—some drugs boost receptors (known as agonists) and some drugs block receptors (known as antagonists) and some are partial boosters and blockers of receptors…(known as partial agonist/antagonists) 3 EXAMPLE: Serotonin Receptors…(17 at last count) • Chemical name? 5‐Hydroxytryptamine (5‐HT) • 7 different types of receptors with subtypes • 5‐HT 1,5‐HT 2, 5‐HT 3, 5‐HT 4,5‐HT 5, 5‐HT 6, 5‐HT 7 • Subtypes—5HT 1A, 1B…5‐HT 2A, 2B, 2C… • Yada, yada, yada… Famous serotonin agonists of 5‐HT2A • LSD (“Lucy in the sky with diamonds” (Lysergic acid diethylamide)(acid, blotter, microdot), “magic” mushrooms, mescaline, PCP (angel dust) are famous 5‐HT2A agonists causing the release of excess serotonin and dopamine—resulting in schizophrenic‐ like effects—hallucinations, psychosis • Drugs that block 5‐HT2A receptors are used to block hallucinations, psychosis—clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and more…FGA and SGA Famous serotonin antagonists of 5‐HT2A and 5‐HT2C • Drugs that block the 5‐HT 2c receptor contribute to weight gain, and increase the susceptibility to insulin resistance, type 2 diabetes, and hyperlipidemia • The second generation atypical antipsychotics (SGAs), Clozaril (Clozapine) and Olanzapine (Zyprexa) block the 5‐HT 2c receptor • clozapine (20% or more weight gain over time); olanzapine (30% of patients gain at least 7% of their initial weight) • Need to monitor weights (BMI) monthly x 3 months) and cholesterol (12 weeks, 1 year, 5 years) when patients are taking these SGAs 4 Weight gain risk from the atypical anti‐ psychotics • Weight gain risk is primarily in first 6 months of taking the drug and is not dose‐ related‐‐The likelihood that a certain medication will cause weight gain or other side effects varies from person to person. • Clozapine (Clozaril)—High • Olanzapine (Zyprexa)—H • Quetiapine (Seroquel)—Medium • Paliperidone (Invega)—M • Risperidone (Risperdal)—M • Aripiprazole (Abilify)—Low • Lurasidone (Latruda)—L • Ziprasidone (Geoden)—L • (Haddad P. Antipsychotic Medications and Weight Gain. Brit Assoc Psychopharm, March 31, 2017) How to negate the weight gain and secondary diabetes • Start the patient on Metformin 500 mg/day* (Glucophage) along with the atypical antipsychotics to negate the weight gain and subsequent diabetes and hyperlipidemia (Wu) • Actually start with 500 mg to reduce GI side effects; titrate up to 1000 mg Drugs and Serotonin Receptors • Drugs that affect serotonin either boost the receptors or block the receptors…agonists or antagonists • 5‐HT1A—boosting this receptor makes you happy (SSRIs) • 5‐HT2A – sexual dysfunction and insomnia (SSRIs) • 5‐HT1B, 1D, 1F—if you boost these receptors vasoconstriction will occur as well as the blockade of neuropeptides released from trigeminal nerve endings that mediate migraine pain; the “triptans” interact with these receptors are used in the treatment of acute migraine headaches 5 Serotonin‐‐Happy and positive self‐esteem • With just the right amount of serotonin individuals experience clear thinking and increased self‐confidence along with social success; the brain balances aggressiveness with assertiveness—leaders and achievers; enough aggression is allowed to surface so that they can be assertive Serotonin plays a role in impulsive eating disorders such as bulimia nervosa • Boosting serotonin improves impulse control—helps control eating disorders including: • Bulimia (be aware of girls with Type 1 diabetes and bulimia) • Binge‐eating disorder • Fluoxetine (Prozac) • Paroxetine (Paxil) Nausea, vomiting, gastric motility, gastric hypersensitivity—5‐ HT3 receptors • Serotonin is released from the duodenum and interacts with the 5‐ HT3 receptors to induce nausea; serotonin and the 5‐HT3 receptors in the CTZ (chemoreceptor trigger zone) in the brainstem induces vomiting • 5‐HT3 antagonists –the “setrons”—ondansetron (Zofran), granisetron (Kytril), dolasetron (Anzemet), palonesetron HCl (Aloxi)(long‐acting) • Chemotherapy (many types), anesthesia, trigger serotonin release from these areas‐‐post‐anesthesia N & V, chemotherapy‐induced N & V, migraine headaches and N & V • Side effect of constipation due to slowing of gastric motility 6 Serotonin and Irritable bowel syndrome (IBS) • Defined as pain or discomfort occurring in association with altered bowel habits over 3+ months • Brain‐bowel connection • Too little serotonin? Constipation‐predominant‐‐IBS‐C • Too much serotonin? Diarrhea‐predominant—IBS‐D • Some individuals have a “mixed” IBS • Treatment? Irritable bowel syndrome (IBS)—some treatments based on serotonin excess or deficiency • SSRIs for IBS‐C – boost serotonin receptors in the bowel, increasing GI motility • Tricyclics for IBS‐D (amitryptyline)(anti‐cholinergic effects)—slows intestinal motility • Loperamide (Imodium) for IBS‐D • Ondansetron (Zofran)(5‐HT3 blocker) for IBS‐D • Viberzi (eluxadoline) for IBS‐D—(doesn’t work on serotonin) (boosts mu {opiate} receptors) to slow GI motility, decreases GI hypersensitivity Serotonin and Premenstrual dysphoric disorder (PMDD) • More women are admitted to psychiatric units in the week immediately prior to menses that any other week. • SERIOUSLY??? • In one study, 47% of admissions occurred during this week (The Carlat Psychiatry Report, February 2014; Targum SD, et al, J of Affect Disorders, 1991;22(1‐2):49‐53) 7 PMDD—3‐8% of women • PMS? 80% of women—”I’m a little more moody the week before my period, but it’s not a big deal.” • PMDD— “I will kill you if you make another sound…” is a severe form of PMS that includes mood swings, depressed
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