Neurotransmitter Acetylcholine PDF

Neurotransmitter ± acetylcholine ( Ach ) Cholinergic receptor ± receptor sites on effectors that respond to acetylcholine ‡ Cholinoceptors: - muscaranic - nicotinic PARASYMPATHETIC NERVOUS SYSTEM RECEPTOR LOCATION EFFECT...

Neurotransmitter ± acetylcholine ( Ach ) Cholinergic receptor ± receptor sites on effectors that respond to acetylcholine ‡ Cholinoceptors: - muscaranic - nicotinic PARASYMPATHETIC NERVOUS SYSTEM RECEPTOR LOCATION EFFECT EFFECT M-1 M-1 Upper G GIT IT Acid ssecretion ecretion Cholinergic ner nerves rves Stimulation S timulation M-2 M-2 Heart (-) inot inotropic, tropic, chronotro chronotropic, opic, dromotropic drromotropic Cholinergic Ch holinergic nerves Stimulation n M-3 M-3 Exocrine Glands Glands (saliva (salivary, ary, Increease secretions Increase secretions (salivation, (saalivation, sweat, lacrimal, lacrimaal, bronchial, bronchhial, llacrimation, acrimation, etc.)) intestinal, etc) Bronchoconstriction B ronchocon nstriction Lungs Increase Increaase motility~diar motility~diarrhea rrhea Eyes Miosis M iosis PARASYMPATHETIC NERVOUS SYSTEM RECEPTOR LOCATION EFFECTT Nm Nm Neuromuscular Neuromu uscular Muscle M uscle co contraction ontraction endplate Nn Nn CNS ganglia CNS C NS Stimu Stimulation ulation Synthesis and Release of Acetylcholine 1. synthesis of acetylcholine - transport of choline inhibited by hemicholinium 2. uptake into storage vesicles - protected from degradation - BLOCKED by VESAMICOL 3. release of neurotransmitter - botulinum toxin- blocks release - spider venom- promotes release 4. binding to receptor 5. degradation by acetylcholinesterase AchÆ acetate + choline PARASYMPATHETIC NERVOUS SYSTEM 11.. Synthesis ‡ ((-) -) Hemicholinium Hemicholinnium 2. S Storage torage ‡ (-) Vesamicol Vesamicol 3. Release Rellease ‡ (-) Botox 44.. Receptor binding binding 5. Removal Remmoval 1. 1. Diffusion 2. Metabolism Mettabolism 3. 3. Reuptake Reuptake 1. Cholinergic ² parasympathomimetic 2. Anticholinergic ² parasympatholytic ƒ drugs that stimulate the parasympathetic NS ƒ mimic Acetylcholine ƒ selective cholinergic drugs for the muscarinic receptors that do not affect the nicotinic ƒ SYNONYMS: cholinergic agonist, cholinergic stimulant, cholinomimetic D- IARRHEA U- RINATION M- IOSIS B- RADYCARDIA B-RONCHOCONSTRICTION E- MESIS/ EXCITATION L- ACRIMATION S-ALIVATION/ SWEATING  Two classes: 1. Direct acting Cholinergic agonist 2. Indirect acting Cholinergic agonist  PARASYMPATHETIC AGONISTS DIRECT-ACTING INDIRECT-ACTING INDI DIRE DIRECT-ACTING RE CHOLINE CH HOLINE ESTERS ALKALOIDS A ALKALOIDS REVERSIBLE REV REVERSIBLE IRREVERSIBLE ALCOHOL ALCOHOL CARBAMATES CARBAM MAT ATE ES ORGANOPHOSPHATES ORGA ANO NOPPHOSPHATES 1. Acetylcholine 1. Pilocarpine 2. Bethanechol 2 2. Muscarine 3. Methacholine 3. Nicotine N cotine Ni 4. Carbachol EDROPHONIUM EDR ROPHONIUM µ-WLJPLQHV´ µ-phates 1. Esters of Choline/choline esters Acetylcholine Betanechol Methacholine chloride Carbachol chloride 2. Alkaloids Pilocarpine Nicotine Muscarine Two classes: 1.Reversible edrophonium Alcohol ± Carbamates ± Physostigmine and Neostigmine 2.Irreversible ± Organophosphates: Isofluorophate and echothiophate Reversible cholinesterase inhibitors Intermediate acting cholinomimetic (CARBAMATES) Drugs for Myasthenia gravis Neostigmine Pyridostigmine Ambenonium Drugs for Glaucoma Demecarium Physostigmine 1. Edrophonium (Tensilon) ƒ - diagnosis of MG ƒ (Tensilon test- inc. strength, dec. ptosis) ƒ *Spider venom- promotes release of acetylcholine Using Tensilon test Myasthenia gravis - underdose underdoose - progr progression ression of the the diseasee Cholinergic crisis - overdose - fascic fasciculation culation - ffatigue atigu ue Muscle weakness + edrophonium= improve improv impro p ve (m ((myasthenia myastheenia gravis) gravis) = worsen ( cholinergic crisis)   ǯ  ƒ Donepezil (Aricept) ƒ Tacrine (Cognex) ƒ Rivastigmine (Exelon) ƒ Galantamine (Reminyl) INSECTICIDES ƒ MALATHION ƒ PARATHION Cevimeline (Evoxac) ƒ for treatment of dry mouth associated with   ǯ•›†”‘‡ Smoking déterrent ƒ Varenicline, Nicotine Soman, sarin, tabun ƒ Nerve gas, used exclusively in warfare & terrorism PARASYMPATHETIC NERVOUS SYSTEM CHOLINOCEPTOR ANTAGONIST MUSCARINIC Antagonist NICOTINIC Antagonist Red R ed as a beet bee et Hot H ot as hell hell Dry D ry as a bone bone Blind B lind as batt Ganglion Neuromuscular Mad a as s hatter blockers junction blockers CHOLINOCEPTOR ANTAGONIST Synonyms: Cholinergic antagonist Cholinergic blocker Anticholinergic Parasympatholytic Antimuscarinic/antinicotinic ƒ Red as a beet ƒ Hot as hell ƒ Dry as a bone ƒ Blind as bat ƒ Mad as hatter ƒ Muscarinic antagonist acting as INVERSE agonists Atropine Pirenzepine Trihexyphenidyl Ipratropium Glycopyrrolate Scopolamine (mmethyl derivaative) ethyl derivative  Cholinergic poisoning Antimuscarinic Cholinesterase therapy regenator Pralidoxime (PAM) Atropine Diacetylmonoxime (DAM) Obidoxime According to the nicotinic receptors they block: 1. Ganglionic blockers inhibit NN 2. Neuromuscular blockers inhibit NM 1. Tetraethylammonium (TEA) 2. Hexamethonium ("C6") 3. Decamethonium, the "C10" analog of hexamethonium  PHARMACOLOGY REVIEW ‡ Starting in House Rules: 11.. Be attentive, attenntive, avoid unnecessary unnnecessary aactivities. ctivities. 10 2. Prepare a pen and a notepad. Most minutes details detaails aree iinn the hand handout, dout, iiff in case thethere ere are additional additional notes, nootes, the the lecturerr will will aler alert rt youu to jot do down own tthe notes. he said no otes. 3. The topics throughout the lecture are divided str strategically. rateggically. There willwill bbee a 2 to End 5-minute break every after a topic. And thatt is followed bbyy practice questions to And to asssess whether assess whhether you aree learning. learning. 236 4. Question and answer portion will follow after afte er everyy topic. toopic.  SEIZURES characterizzed b characterized byy an excessive, ex hypersynchronous xcessive, hypersynchrono ous discharge of cortical neuron n euron activity, activity, measured which can bee m easured d by the ELECTROENCEPHA ALOGRA ELECTROENCEPHALOGRAM AM (EEG). (EEG). CONVULSIONS ‡ violent, involuntary contractions of the voluntary muscles. ‡ * A patient may have epilepsy or a seizure disorder without convulsions. EPILEPSY ‡ a chronic seizure disorder, or group of disorders, characterized by seizures that usually recur unpredictably in the absence of a consistent provoking factor. Phases of seizure ‡ Prodrome ‡ Ictal ‡ Post-ictal INTERNATIONAL CLASSIFICATION OF EPILEPTIC SEIZURES I. PARTIAL SEIZURES ‡ most common seizure type ‡ occurring in approximately 80% of epileptic patients. ‡ clinical and EEG changes indicate initial activation of a system of neurons limited to part of one cerebral hemisphere that may spread to other or all brain areas. CLASSIFICATION OF PARTIAL SEIZURES ‡ SIMPLE PARTIAL SEIZURES ‡ generally do not cause caause loss of consciousness. co onsciousnesss. ‡ SIGNS AND SYMPTOMS: primarily motor, sensory, somatosensory, autonomic or behavioral. CLASSIFICATION OF PARTIAL SEIZURES ‡ COMPLEX PARTIAL SEIZURES ‡ accompanied by impaired consciousness; however in some cases, tthe he impairm impairment ment precede precedes es or or followss the the seizure. COMPLEX PARTIAL SEIZURES ‡ MANIFESTATIONS ‡ Purposeless behavior behavvior is common. commo on. ‡ The affected person mayy h ave a glassyy stare, have stare, mayy wand der about aimlessly, and mayy speak wander speak unintelligibly. uninttelligibly. ‡ Psychomotor Psychomottor (temporal lobe) lo obee) epilepsy may may lead lead to aggrressive behavior aggressive beh havior (e.g., outburstss ooff rrage age or vioolence). violence). II. GENERALIZED SEIZURES ‡ diffuse, affecting both cerebral hemispheres. ‡ clinical and EEG changes indicate initial involvement of both hemispheres. GENERALIZED SEIZURES ‡ ABSENCE (Petit mal) SEIZURES ‡ present as alterations alteratiions of consciousness conscio ousness (absences) (abssences) lasting 10-30 seconds. ‡ Staring (with occasional eye blinking) and loss or reduction in postural tone is typical. ‡ Enuresis  GENERALIZED SEIZURES ‡ 2. MYOCLONIC SEIZURES (bilateral massive epileptic myoclonus) ‡ present as involuntary jerking jerking ooff tthe he facial,, limb, limb, or trunk trun nk muscles, possibly in rhythmi rhythmicic manner. GENERALIZED SEIZURES 3. CLONIC SEIZURES ‡ characterized by sustained su ustained mus muscle scle contractions contracttions alternating with relaxation 4. TONIC SEIZURES ‡ involve sustained tonic muscle extension (stiffening). GENERALIZED SEIZURES ‡ 5. GENERALIZED TONIC-CLONIC SEIZURES (grand mal) ‡ cause sudden loss of consciousness. co onsciousness. GENERALIZED TONIC-CLONIC SEIZURES (grand mal) ‡ The individual becomes rigid and falls to the ground. Respirations are interrupted. The leg extended, and the back arches; contraction of the diaphragm may induce grunting. This tonic phase lasts for about 1 minute. GENERALIZED TONIC-CLONIC SEIZURES (grand mal) ‡ A clonic phase follows, marked by rapid bilateral muscle jerking, muscle flaccidity, and hyperventilation. Incontinence, tongue biting, tachycardia, and heavy salivation sometimes occur. ‡ Some epileptics have serial grand mal seizures, regaining consciousness briefly between attacks. In some cases, grand mal seizures occur repeatedly with no recovery of consciousness between attacks (status epilepticus) GENERALIZED SEIZURES ‡ 6. ATONIC SEIZURES (drop attacks) ‡ characterized by a ssudden udden loss of of postural tone tone so thatt the individual falls to the ground. They occur primarily in children. ch hildren. Classification based on Etiology ‡ PRIMARY (idiopathic) SEIZURES ‡ have no identifiab identifiable ble cause. ‡ SECONDARY SEIZURES (symptomatic or acquired seizures) ‡ occur secondary to an identifiable cause. SECONDARY SEIZURES ‡ Infectious diseases (meningitis, influenza, toxoplasmosis, mumps, measles, syphilis) ‡ High fever (in children) ‡ Head trauma ‡ Metabolic disorders (hypoglycemia, hypocalcemia) ‡ Alcohol or drug withdrawal  ANTIEPILEPTIC DRUG CLASSIFICATIONS BARBITURATES BA ARBITURATES HYDANTOINS SUCCIM SUCCIMIDES MIDES Phenob Phenobarbital barbital Phenytoin Ethos Ethosuximide suximide Primidone Mephenytoin Mepphenyytoin M Methsuximide ethsuximide e Mephobarbital Ethotoin Phensuxim Phensuximide mide Fosphenytoin Zonisamide Zoniisamide OXAZOLIDINEDIONES OX XAZOLIDIN NEDIONES BENZODIAZEPINE BENZO ODIAZEPIN NE MISC MISCELLANEOUS CELLANEOUS Parameth Paramethadione had dione Clonaz Clonazepam zepam L Lamotrigine amotrigine Trimeth hadione e Trimethadione Diazep pam Diazepam Felbamate Gabapentin Gabap pentin TYPE DRUG DRUG OF CHOICE CH HOICE Carbamazepine Carbbamazepine Absence Abs sence ETHOSUXIMIDE Valproic V alproic acid ac cid Phenacemide Phenac cemide Abssence W/ Grand Absence d VALPROIC ACID Topiramate T opiramate Maal Mal Tiagabine Tiagabine Grand Gra and Mal PHENYTOIN/CARBAMAZEPINE PHENYTOIN/CARBAMA AZEPINE Levetiracetam Levetiraacetam Myoclonic Myo oclonic Seizure VALPROIC VALPROI IC A ACID CID Febrile Seizure Seiizure PHENOBARBITAL PHENOBARBITA AL Status Epilepticuss LORAZEPAM (current);; DIAZEPA DIAZEPAM AM ((old) old)  PHARMACOLOGY REVIEW ‡ Starting in House Rules: 11.. Be attentive, attenntive, avoid unnecessary unnnecessary aactivities. ctivities. 10 2. Prepare a pen and a notepad. Most minutes details detaails aree iinn the hand handout, dout, iiff in case thethere ere are additional additional notes, nootes, the the lecturerr will will aler alert rt youu to jot do down own tthe notes. he said no otes. 3. The topics throughout the lecture are divided str strategically. rateggically. There willwill bbee a 2 to End 5-minute break every after a topic. And thatt is followed bbyy practice questions to And to asssess whether assess whhether you aree learning. learning. 258 4. Question and answer portion will follow after afte er everyy topic. toopic. Anxiety ‡ is an emotional state commonly caused by the perception of real or potential danger that threatens the security of an individual  GAD-Generalized Anxiety Disorder ‡ Excessive and uncontrollable anxiety and worry  GAD-Generalized Anxiety Disorder ‡ Anxiety and worry, associated with three of the following symptoms: a. restlessness restleessness b. fatigue difficulty culty in concentrating c. diffic con ncentrating d. irritability e. musc muscle cle tension f. sleep d disturbance isturbance PANIC DISORDER ‡ It begins as a series of spontaneous, unexpected panic attacks, involving an intense, terrifying fear, similar to that caused by life-threatening danger.  Diagnostic Criteria for Panic Attacks ‡ At least four of the following symptoms developed abruptly and reached a peak within 10 minutes: Palpitations or tachycardia Dizziness, unsteadiness, Sweating lightheadedness Trembling or shaking Derealization or Sensations of shortness of depersonalization breath or smothering Feeling of choking Fear of losing control Chest pain or discomfort Fear of dying Nausea or abdominal Paresthesia distress Chills or hot flushes ‡ Severe and pervasive anxiety about being in situations from which escape might be difficult such as being ĂůŽŶĞŽƵƚƐŝĚĞŽŶĞ͛ƐŚŽŵĞ͕ traveling in a car or bus, or being in a crowded area Specific phobia- intense fear of particular objects or situations (e.g. snakes, heights); most common psychiatric disorder - AGORAPHOBIA - Severe and pervasive anxiety about being in situations from which escape might be difficult such as being alone ŽƵƚƐŝĚĞŽŶĞ͛ƐŚŽŵĞ͕ƚƌĂǀĞůŝŶŐŝŶĂĐĂƌŽƌďƵƐ͕ or being in a crowded area Post-traumatic stress disorder- persistent reexperience of a trauma, efforts to avoid recollecting the trauma, and hyperarousal Obsessive-compulsive disorder- recurrent obsessions and compulsions that cause significant distress and occupy a significant ƉŽƌƚŝŽŶŽĨŽŶĞ͛ƐůŝĨĞ TREATMENT ‡ A. Goals of Therapy: ‡ to reduce the severity, duration and frequency of the anxiety symptoms ‡ ƚŽŝŵƉƌŽǀĞƚŚĞƉĂƚŝĞŶƚ͛ƐŽǀĞƌĂůů functioning ‡ to prevent anxiety symptoms ‡ to improve quality of life ‡ Nonpharmacologic Therapy ‡ Short-term counseling ‡ Stress management ‡ Psychotherapy - for encouragement ‡ Meditation ‡ Exercise ‡ Avoidance from caffeine, nonprescription stimulants and diet pills ‡ Pharmacologic Therapy  What are CALMING Sedative- hypnotic EFFECT drugs? Sedative-hypnotic drugs SLEEP Tranquilizers Sedative-Hypnotics/Anxiolytics 1.Benzodiazepines 2.Barbiturates 3.Z-drugs (Zolpidem, Zaleplon, Eszopiclone) 4.Ramelteon 5.Buspirone Benzodiazepines Use/s Ultra-short Pre-medication Midazolam acting Short to Anxiolytics Alprazolam Intermediate Sedative- Lorazepam acting Hypnotics Flunitrazepam Long- acting Anticonvulsants Clonazepam Diazepam Barbiturates Use/s Ultra-short Pre-medication Thiopental acting Short to Sedative- Secobarbital Intermediate Hypnotics Pentobarbital acting Amobarbital Butabarbital Long- acting Anticonvulsants Phenobarbital Mephobarbital Newer Hypnotics ‡ Eszopiclone (Lunesta Ρ) ‡ cyclopyrrolone ‡ Zaleplon ( Sonata Ρ) Used in ‡ pyrazolopyrimidine pyrazollopyrimidine SLEEP ‡ Zolpidem (AmbienΡ) ‡ Imidazopyridine disorders Buspirone ‡ It is an alternative ffor or GAD to patients who cannott tolerate tolerate the sedating effects and psychomotor psychomotor impairmentt of of BZs. ‡ The agent of choice in the management manage ement of chronic, chrronic, persistent persisttent anxiety. ‡ It is not cross-tolerant cro with ith BZs and oss-tolerant wi d will nott ttreat prevent reat or preve ent symptoms of of BZ withdrawal. ‡ BZ dose should shou uld be tapered before switchi switching ing to busp buspirone. pirone. ‡ It It iiss an appropriate choice e ffor or anxio anxious ous pat patients tients with a h history istory of alcohol alcoh hol or drug abuse. Ramelteon (RozeremΡ) ‡ Melatonin Receptor Agonist ‡ MOA: Activates MT1 MT1 and MT2 receptors receptors in suprachiasmatic nuclei in the CNS ‡ Rapid Rapiid onset onse et of effect with h minimal minimal rebound rebo ound insomnia insomniaa  ADRENERGIC BLOCKING AGENTS ‡ Propranolol and other beta-blockers may be useful in patients with prominent cardiovascular symptoms of anxiety. ‡ They are less effective anxiolytics than BZs, and their usefulness may be restricted to those anxiety patients with physical symptoms, especially cardiovascular complaints, have not adequately responded to BZ therapy. ADRENERGIC BLOCKING AGENTS ‡ Propranolol,10 mg bid should be used initially and gradually titrated to anxiolytic response. ‡ Discontinuation should be gradual to avoid rebound anxiety and cardiovascular effects. Old Sedative- Hypnotics ‡ CHLORAL HYDRATE ‡ Associated to MICKEY FINN ‡ Trichloroethanol ʹ active metabolite ‡ Trichloroacetic acid ʹ toxic metabolite ‡A Accumulate ccumulate with the th he nightly nightly administration administtration of th the he drug d rug 1. This is a drug which reduces anxiety and induces calmness. 2. DOC for chronic anxiety. 3. Barbiturate which is used as pre-medication for anesthesia 4. It is the loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories before the event remain intact. 5. A type of metabotropic receptor wherein the interaction occurs within the membrane. 6. Drug of choice for benzodiazepine poisoning 7. Toxic metabolite of chloral hydrate 8. Severe and pervasive anxiety about being in situations from which escape might be difficult 9. Major inhibitory neurotransmitter of the CNS.