MATA| PHAR 140 NS DIVISION 1. Central Nervous System (CNS) - brain, spinal cord 2. Peripheral Nervous System (PNS) - neurons outside the brain & spinal cord PNS DIVISION A. Somatic - voluntary regulation of skeletal muscles B. Autonomic - involuntary regulation of smooth muscle, cardiac muscle & glands I. Sympathetic II. Parasympathetic AUTONOMIC PHARMACOLOGY -usingdrugsthatmimicorblocktheactionsofchemicaltransmittersto selectively modify many autonomic functions --involveavarietyofeffectortissues(cardiacmuscle,smoothmuscle, vascular endothelium, exocrine glands, and presynaptic nerve terminals) AUTONOMIC NERVOUS SYSTEM SYMPATHETIC /ADRENERGIC (Fight, Flight, Fright) PARASYMPATHETIC / CHOLINERGIC (Rest & Digest) Eye Pupils Ciliary muscleDilation (far vision) Constriction (near vision) Bronchial smooth muscle BronchodilationBronchoconstriction Heart(+) chronotropic(+) inotropic(-) chronotropic (-) inotropic GIT Sphincters Intestinal wall muscle Secretions Closed motility Opened motility Bladder Sphincter Wall muscles ClosedRelaxation OpenedContraction Male genitaliaEjaculationErection UterusContractionRelaxation SYMPATHETIC /ADRENERGIC (Fight, Flight, Fright) PARASYMPATHETIC / CHOLINERGIC (Rest & Digest) Salivary glandsThick, viscid secretionCopious, water secretion Lacrimal glandsSecretion Vascular smooth muscle Skin / gut Skeletal muscle Constriction Dilation Skin Pilomotor muscles Sweat glands Contraction sweating Metabolic fxns Liver Fat cells Kidney GluconeogenesisGlycogenolysisLipolysisRenin release CHOLINERGIC RESPONSE Diarrhea Urination MiosisBradycardiaBronchoconstrictionEmesis LacrimationSalivation Sweating ALICE IN WONDERLAND Hot as a hare: hyperthermia, fever Red as a beet: tachycardia, vasodilation/flushing Blind as a bat: blurring of vision, cycloplegia, mydriasis Mad as a hatter: delirium, hallucinations Dry as a bone: decreased gland secretions Autonomic Transmission - involves two neurons: 1. Presynaptic neurons extend from the brain to autonomic ganglia where they transmit CNS signals to postsynaptic neurons by releasing acetylcholine into the synaptic cleft 2. Postsynaptic neurons subsequently transmit impulses to end organs by releasing norepinephrine or acetylcholine SYMPATHETIC /ADRENERGIC (Fight, Flight, Fright) PARASYMPATHETIC /CHOLINERGIC (Rest & Digest) Anatomy Roots Thoracolumbar (T1-T12, L1-L5) Craniosacral (CN 3, 7, 9 & 10, S3-S4) Location of GangliaNear the spinal cordNear the target organ Length of Fibers Preganglionic Postganglionic Short Long Long Short Neurotransmitters Preganglionic Postganglionic Acetylcholine NE, Epinephrine, Dopamine Acetylcholine Acetylcholine Receptor Ganglia Target Organ Nicotinic Alpha, Beta, Dopamine Nicotinic Muscarinic, Nicotinic MATA| PHAR 140 CHOLINERGIC TRANSMISSIONDRUGSADRENERGIC TRANSMISSIONDRUGS Synthesis Molecules Enzyme Reaction Choline- outside cell (transported by Na+-dependent membrane CHT) RLS Acetyl CoA- mitochondria Choline acetyltransferase (ChAT) Acetylation Hemicholinum- inhibits transport 1.Tyrosine Dopa (RLS) 2.Dopa Dopamine (dopaminergic neurons) 3.Dopamine Norepinephrine (sympathetic postganglionic neurons) 4.Norepinephrine Epinephrine (adrenal medulla) 1 Tyrosine hydroxylase (TH) 2 Dopa decarboxylase (DD) 3 Dopamine--hydroxylase (DH) 4 Phenylethanolamine-N-methyltransferase (PNMT) Metyrosine/-methyltyrosine- inhibits TH Carbidopa- inhibits DD Storage Carrier Vesicle-associated transporter (VAT) Vesamicol- inhibits transport DA NE Vesicular monoamine transporter (VMAT) Reserpine-depletes transmitter stores ReleaseVoltage-sensitive Ca+2 -channels in the terminal membrane are opened influx of Ca+2 -latrotoxin- promotes Ca+2 release botulinum toxin- inhibits release Action potential influx of Ca+2 Release of NE, cotransmitters, ATP and DH NE diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter (NET)Guanethidine, Bretylium- blocks release ReceptorAcetylcholine receptor/Cholinoceptor AdrenoceptorsAmphetamines, methamphetamines, tyramine, ephedrine - promote release INCREASED NE ACTIVITY Removal Enzyme Reaction Acetylcholinesterase (AchE) Hydrolysis Choline + Acetate Monoamine oxidase (MAO) Catechol-O-methyltransferase (COMT) Oxidation (MAO) Methylation (COMT) Metabolites: 3-methoxy-4-hydroxy-mandelic acid / vanillylmandelic acid (VMA) metanephrine,normetanephrine Cocaine,TCA- blocks reuptake INCREASED NE ACTIVITY CHOLINOCEPTORS Muscarinic Receptors M3Exocrine glands secretion Smooth muscles contraction EyeMiosis, ocular accommodation Blood vessels (endothelium) VasodilationCNS M4CNSEnhanced locomotion M5CNS Salivary glands Iris / ciliary muscle Nicotinic Receptors CHOLINERGIC DRUGS/CHOLINOMIMETICS 1. Cholinergic Agonists -Direct-acting- bind, activate receptor -Indirect-acting- inhibit AChE ACh 2. Cholinergic Antagonists DIRECT-ACTING CHOLINERGIC AGONISTS - choline bound to an acetyl derivative by an ester bond - poorly absorbed & poorly distributed into the CNS ReceptorLocationEffect M1Exocrine glandsSecretion Autonomic ganglia seizure activity CNS cognitive and function (learning and memory) M2HeartCardiac inhibition CNSNeural inhibition tremors; hypothermia; analgesia Smooth muscle contraction Peripheral nerves Neural inhibition ganglionic transmission ReceptorLocationEffect N1GanglionStimulation CNSNeurotransmission Skeletal muscleContraction MATA| PHAR 140 DIRECT-ACTING CHOLINERGIC AGONISTS DrugPropertiesIndicationAdministrationAdvantages/Disadvantages Acetylcholine (most potent) -ester of acetic acid & choline, a quaternary amino alcohol -both muscarinic and nicotinic (M1M5) - prototype cholinergic agonist Miotic agent in cataract surgery (10 min) *CARBACHOL long duration (1 hr) Limited therapeutic use 1.Rapid hydrolysis 2.Lack of selectivity Bethanecol*-strongly muscarinic(M1-M3) Acute non-obstructive urinary retention Increase intestinal motility after surgery PO, SC Duration: 1 hr More hydrolysis-resistant MUSCARINIC CHOLINOMIMETICS mediate contraction of: -pupillary constrictor muscle (miosis)-ciliary muscle (accommodation of focus for near vision) *puts tension on the trabecular meshwork, opening its pores & facilitating outflow of the aqueous humor into the canal of SchlemmCarbachol-ester of carbamic acid -muscarinic & nicotinic activity (M1-M5) -open-angle glaucoma that is resistant to pilocarpine Ophthalmic (topical, intraocular) Duration: 1 hr More hydrolysis-resistant Methacholine/ Provocholine* -muscarinic & weak nicotinic activity Dx of asthma (Methacholine challenge) Inhalation *give rapid-acting bronchodilator after test More hydrolysis-resistant Pilocarpine-Pilocarpus sp. -tertiary amine that crosses membranesrelatively easily -muscarinic activity (M1-M3) -rapidly absorbed by the cornea of the eye -can cross BBB DOC for glaucoma -rapid miosis & contraction: Ciliary muscle -stretches the trabecular network, increasing its porosity & permeability to the outflow of fluid Iris sphincter -pulls the peripheral iris away from the trabecular meshwork, thereby opening the path for aqueous outflow Ophthalmic drops- closed/narrow-angle Gel/ time-release system- open/wide-angle -Unaffected by cholinesterases -S/E: CNS disturbances (lipid-soluble) Muscarine-mushroom Amanita muscaria-muscarinic activity (M1-M3) -some mushrooms of the genera Inocybe,Clitocybe, &Omphalatus contain significantamounts of muscarineNo therapeutic useS/E: nausea, vomiting,headache- causes diarrhea, sweating, salivation, &lacrimation*PARASYMPATHETIC OVERSTIMULATION- mushroom poisoning (DUMBBELSS) INDIRECT-ACTING CHOLINERGIC AGONISTS/ CHOLINESTERASE INHIBITORS 1.Reversible- Edrophonium, Carbamates 2.Irreversible- Organophosphates ORGANOPHOSPHATES- highly lipid-soluble liquids - bind to AChE forming covalent phosphorous-enzyme bond phosphorylated enzyme- spontaneous hydrolysis of a phosphorylated enzyme is generally very slow - phosphorylated enzyme complex maundergo a process called aging Aging - involves the breaking of one of the oxygen-phosphorous bonds of the inhibitor & further strengthens the phosphorous-enzyme bondIsofluorophatediisopropylfluorophosphate (DFP) Chronic treatment of open-angle glaucoma Duration: 1 week Echothiophate -phospholine iodide - highly polar Open-angle glaucomaDuration: 100 hours Malathion, Parathion-thiophosphate prodrugs- insecticides active metabolites: malaoxon, paraoxon Tabun, Sarin, Soman-nerve gases -chemical warfare ANTIDOTESCholinergic crisis MATA| PHAR 140 Pralidoxime chloride (2-PAM) *Pyridine-2-Aldoxime Methylchloride - strong nucleophile- quaternary amine - able to break the phosphorous-enzyme bond

Cholinesterase regenerator drug * quaternary ammonium group binds to the anionic site of the enzyme & thereby promotes dephosphorylation IV Should be given before aging - does not cross the blood-brain barrier not useful for reactivating cholinesterases inthe CNS Atropine Anticholinergic agentMuscarinic blocker IV CARBAMATES -contain a tertiary or quaternary amine group that can bind noncovalently to the anionic site of the enzyme carbamylated enzyme-carbamylated enzyme undergoes hydrolysis much more slowly (30 minutes to 6 hours) Physostigmine/Eserine-alkaloid obtained from the Calabar or ordeal bean (Physostigma venenosum) -a tertiary amine of greater lipid solubility -Intestinal & bladder atony-Miotic agent for open-angle glaucoma - Tx of overdoses of drugs with anticholinergic actions (Atropine, TCA,Phenothiazine) Myasthenia gravis -muscle weakness & rapid fatigue of muscles during use -affects skeletal muscle neuromuscularjunctions - autoimmune process causes production ofantibodies that bind to the subunits of thenicotinic receptor -accelerated degradation of the receptor -blockage of acetylcholine binding to receptors onmuscle end plates -opthalmic, IV, IM Duration:0.5-2 hours -can enter & stimulate the CNS -can inhibit AChE in the CNS -stimulates not only muscarinic & nicotinic sitesof the ANS but also the nicotinicreceptors ofthe neuromuscular junction Neostigmine/Prostigmin-quaternary ammonium carbamate- more polar & therefore does not enter theCNS -direct agonist activity at NM - Myasthenia gravis- Paralytic ileus or atony of the urinary bladder - Antidote for tubocurarine poisoning & othercompetitive neuromuscular blocking agents- PO, SC - duration: 0.5-2 hours Pyridostigmine/Mestinon-quaternary ammonium carbamate- has direct agonist activity at NM-chronic management of myasthenia gravis - PO, IV, IM - duration: 3-6 hours Carbamate Insecticides: Carbaryl, Propoxur (Baygon), Aldicarb QUATERNARY AMINE Edrophonium/Tensilon-reversibly bind electrostatically & by hydrogenbonds to the active site, thus preventingaccess of acetylcholine -diagnosis of myasthenia gravis (Tensilon Test) 1.Obtain baseline measurements of muscle strength 2.Initial Dose: 2mg IV 3.If no reaction occurs after 45 seconds, an additional 8mg may be injected.4.Observation: improvement in muscle strength that lasts about 5 minutes -DDx of MG and hypercholinergic crisis (w/cproduces depolarization blockade of theNMJ) - cholinergic crisis: further weakening ofmuscles Short duration of action (5-15 minutes) CHOLINERGIC ANTAGONISTS -cholinergic blockers MATA| PHAR 140 - anticholinergic drugs - block the actions of ACh at muscarinic or nicotinic cholinoceptorsI.Muscarinic BlockersII. Neuromuscular Blockers/Skeletal Muscle Relaxants III.Ganglionic Blockers CHOLINERGIC RESPONSE Diarrhea Urination MiosisBradycardiaBronchoconstrictionEmesis LacrimationSalivation Sweating ALICE IN WONDERLAND Hot as a hare: hyperthermia, fever Red as a beet: tachycardia, vasodilation/flushing Blind as a bat: blurring of vision, cycloplegia, mydriasis Mad as a hatter: delirium, hallucinations Dry as a bone: decreased gland secretions -block nicotinic receptors in muscles paralysis Classification: A.Nondepolarizing blockers - competitive blockers - combine with the nicotinic receptor & preventthe binding of ACh- prevent depolarization of the muscle cell-membrane & inhibit muscular contraction *Overcome by increasing the concentration of ACh in the synaptic gap ORDER OF PARALYSIS: 1 Face, eye, fingers 2 Limbs, neck, trunk 3 Intercostal & diaphragm muscles B.Depolarizing blocker MOA: Phase I - opening of the sodium channel associatedwith the nicotinic receptors - depolarization of the receptor - fasciculationsPhase II - gradual repolarization as the sodium channel closes or is blocked - resistance to depolarization - flaccid paralysis ORDER OF PARALYSIS 1. Fasciculations in chest & abdomen 2. Neck, arms, legs 3. Facial, pharynx, larynx 4. Respiratory muscles - Ng antagonists - block nicotinic receptors in both sympathetic &parasympathetic ganglia *ACh: neurotransmitter in all sympathetic & parasympathetic ganglia - reduce the effects of whichever system ispredominant - seldom used clinically Sympathetic blocking effects ArteriolesDilate, high flow, hypotension VeinsDilate, pool blood, low return, low cardiac output Parasympathetic blocking effects HeartTachycardia IrisMydriasis Ciliary muscleCycloplegia GI tractLow tone, low motility, constipation BladderUrine retention Salivary glandsXerostomiaSympathetic (cholinergic) Sweat glandsanhidrosis MUSCARINIC BLOCKERS DrugPropertiesIndicationContraindicationAdverse Effects/Other Notes Atropine/Hyoscyamine-prototype alkaloid from deadlynightshade (Atropabelladonna) & Jimson weed (Daturstramonium)- central & peripheral muscarinic blocker ( M1-M5) -irritable bowel syndrome -mild diarrhea -GIT & bladder spasms -enuresis -bradycardia-bronchospasm-reduces glandular & bronchiolar secretionsbefore anesthesia -treats intoxication by cholinergic agonists orby acute mushroom poisoning-produces mydriasis & cycloplegia (ophthalmoscopic examination) CI: -glaucoma -prostatic hypertrophy -heart disease -obstructive bowel disease Eye - mydriasis- cycloplegia- outflow resistance GIT - reduces activity of the GIT - motility - secretion of pepsin & acid Urinary system - constriction of sphincter - relaxation of detrusorGlands - salivary, sweat, & lacrimal gland secretions Cardiovascular - bradycardia (low dose) block presynapticmuscarinic receptors that normally provide feedback inhibition of therelease of ACh- tachycardia (higher dose) Adverse effect: reverse DUMBBELSS Scopolamine/Hyoscine-alkaloid from henbane (Hyoscyamus niger) - M1, M2, M3 blocker - produces peripheral effects similar to those ofatropine - has greater action on the -prevents motion sickness (transdermal) - blocks short-term memory- produces amnesia & sedation (obstetrics withmorphine) Adverse effects: -more CNS depression at low doses thaatropine - similar to atropine at high doses MATA| PHAR 140 CNS - longer duration of action than atropine Homatropine Cyclopentolate Tropicamide Ophthalmoscopic examination (produce mydriasis & cycloplegia) Ipratropium bromide-M1, M2, M3, M4 blocker - more peripheral effects, less CNS effects Asthma & chronic obstructive pulmonary disease (COPD) Tiotropium (Spiriva) - treatment for COPD Pirenzepine-M1 blocker -selective for muscarinic receptor in thestomach - poorly absorbed, thus high concentration in gut -- secretion of acid & pepsin Peptic ulcers Adverse effects: few, relatively specific forgastric secretions Benztropine, Trihexyphenidyl, Oxybutynin M1, M2, M3 blockersParkinsons disease, extrapyramidal disorders DicyclomineM1, M2*, M3 blocker *hypermotility of the bowel Propantheline-M1, M2, M3 blocker - reduces GI smooth-muscle spasms [M2 (contraction), M3] adjunct for peptic ulcers *Adjunct- supporting *Adjuvant-additional Other Drugs That Have Anticholinergic Effects: 1. Antihistamines 2. Antipsychotics 3. Tricyclic antidepressants (TCAs) 4. Opioids

Neuromuscular Blockers/Skeletal Muscle Relaxants: NON-DEPOLARIZING BLOCKERS DrugPropertiesIndicationAdministrationAdverse Effects/Other Notes VecuroniumAdjunct to anesthesia: -muscle relaxant -eases intubation & ventilation-eases orthopedic manipulation -controls respiration during chest surgery -IV Short duration of action (25-40 min.) -suitable for short surgical procedures Adverse effects: - usually cardiac stable, but induces: *severe tachycardia *bradycardia*AV block or CHF complications -Very little histamine release Atracuriumuseful in mechanical ventilation of critically illpatients patients with kidney & liver failure *also Cisatracurium (administer slowly due to HA release) short duration of action (20-45 min.) -suitable for short surgical procedures Adverse effect: Moderate histamine release Pancuroniumvagolytic actions (increases HR) Used when elevated heart rate is desired heart rate no histamine release Tubocurarine-from Curare (Strychnos sp.)used as arrow poison in South America Prevents the fasciculations associated with succinylcholine administration IVhypotension (histamine)bronchospasm (ganglionic blockade) Mivacurium-hydrolyzed by plasma cholinesterase Short surgical proceduresshort duration of action (15-20 min.) more rapid recovery from blockade RocuroniumFor tracheal intubation in patients withgastric contents rapid onset of action (1-3 min.) minimal cardiovascular effect Pipecuronium, Doxacurium adjunct to anesthesia in long surgery cases long duration in patients with renal dysfunction minimal cardiovascular effect prolonged neuromuscularblockade DRUG INTERACTIONS I. Cholinesterase Inhibitors - Neostigmine, Physostigmine, Edrophonium- can overcome the action of nondepolarizing blockers II. Halogenated Hydrocarbon Anesthetics - enhance neuromuscular blockade by exertinga stabilizing action at the neuromuscular junction III. Aminoglycoside Antibiotics - inhibit ACh release from cholinergic nerves bycompeting with calcium ions IV. Calcium Channel Blockers - may increase the neuromuscular block of non- depolarizing & depolarizing blockers MATA| PHAR 140 Neuromuscular Blockers/Skeletal Muscle Relaxants: DEPOLARIZING BLOCKERS Succinylcholinerapid hydrolysis by acetylcholinesterase &plasma pseudocholinesterase Used when rapid endotracheal intubation isrequired during the induction of anesthesia -IV, IM rapid onset (30-60 sec.) short duration (3-5 min.) intraocular & gastric pressures - dysrhythmias- post-operative muscle pain - apnea - malignant hyperthermia *muscle rigidity & hyperpyrexia - treatment: -rapidly cooling the patient -Dantrolene - blocks release of calcium from the sarcoplasmic reticulum of muscle cells GANGLIONIC BLOCKERS DrugPropertiesIndicationAdministrationAdverse Effects/Other Notes Nicotineactive ingredient in tobaccosmoking cessation therapytransdermal patch, chewing gum Low dose: causes ganglionic stimulation bydepolarization blood pressure & heart rate motor activity of the bowel High dose: causes ganglionic blockade blood pressureactivity both in the GIT & bladder musculature ceases Adverse Effects: - irritability - tremors - intestinal cramps - diarrhea - heart rate & blood pressure Hexamethonium-produces most of its blockade by occupyingsites in or on the nicotinic ion channel, not byoccupying the cholinoceptor itself introduced clinically as the first drugeffective for management of hypertension Trimethaphanshort-acting, competitive nicotinic ganglionicblocker treatment of hypertensive emergencies caused by pulmonary edema or dissectingaortic aneurysm short-acting Mecamylaminecompetitive nicotinic ganglionic blocker treatment of moderately severe to severehypertension Reversing Neuromuscular Blockade Pre-reversal: - Atropine or Glycopyrrolate- administered prior to reversing agents toprevent bradycardia, salivation & othermuscarinic effects Reversal: - cholinesterase inhibitors - increased ACh concentration competes withneuromuscular blockers