Autonomic Pharmacology

Autonomic Pharmacology
Lecture 1, 2 Autonomic Pharmacology Explain the function and mechanism of action of all elements of the ANS Define the roles of cholinergic receptors, their differences, and systemic responses Differentiate between the actions of muscarinic, nicotinic and adrenergic receptors and their subtypes Identify and explain the mechanism of action for pharmacologic agents used to manipulate these systems, and their role in pharmacotherapy Define the pharmacologic rationale for therapeutic application of autonomic-acting agents Given a generic drug name, define mechanism of action, side effects, and therapeutic utility

Peripheral Nervous System
Autonomic NS Somatic NS Regulates activity of: Smooth muscles Exocrine glands Some endocrine glands Cardiac tissue Metabolic activities Involuntary Regulated by brain stem centers Activates skeletal muscle contraction Voluntary body movements Regulated by corticospinal tracts & spinal reflexes Side note: exocrine- section into external environment through ducts, e.g. (sweat, oil, wax, enzymes, etc.); endocrine- secretion into internal environment with no ducts and hormones are secreted

Preganglionic autonomic neurons and somatic neurons are myelinated
Ach N- ANS preganglionic + somaticNS Ach M- ParaNS postganglionic + SymNS sweat glands **Exception Adrenergic- SymNS postganglionic Concept: ganglia use Ach/neuronal tissue

The adrenal medulla has Ach receptors and acts like a neuronal ganglia
The adrenal medulla has Ach receptors and acts like a neuronal ganglia. It releases NE (80%) and Epi (20%) **Epi is only made by the adrenal medulla by SNS

Enteric Nervous System - part of the PNS
Meshwork of fibers innervating the GI tract Controls GI motility and secretion Has Independent control! And highly regulated by the autonomic nervous system And higher levels of the CNS “Brain of the Gut”

Autonomic Nervous System
Sympathetic NS Nerves arise from the thoracic and lumbar spinal cord Short preganglionic fibers & long postganglionic fibers Parasympathetic NS Portions of cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal) and X (vagus)  all are both sensory and motor except CNIII which is just motor Long preganglionic fibers and short postganglionic fibers

EPSP- Na+ influx- Nicotinics is Na+ channel faster
IPSP- K+ efflux, Cl- influx Muscarinic Receptors Regulate (slow IPSP/EPSP)- 2nd messengers regulate K+ or Cl- channels and are slower Ganglia Phenomenon: have both receptors and Ach can act on both– Nicotinic causes EPSP. When Ach binds to muscarinic they regulate the EPSP and these can be slow IPSP or EPSP regulated by M1 receptors .

Neurotransmission 7 Steps of Synaptic Transmission **all drug targets
Synthesis and storage Action potential and depolarization Activation of voltage-dependent Ca2+ channels Vesicle fusion and release Receptor binding Signal termination in the synaptic cleft Termination of postsynaptic intracellular signaling There are also autoreceptors that determine how the cell will release the NT in presynaptic cell- usually inhibitory Steps in synaptic transmission. Synaptic transmission can be divided into a series of steps that couple electrical depolarization of the presynaptic neuron to chemical signaling between the presynaptic and postsynaptic cells. 1. Neuron synthesizes neurotransmitter from precursors and stores the transmitter in vesicles. 2. An action potential traveling down the neuron depolarizes the presynaptic nerve terminal. 3. Membrane depolarization activates voltage-dependent Ca2+ channels, allowing Ca2+ entry into the presynaptic nerve terminal. 4. The increased cytosolic Ca2+ enables vesicle fusion with the plasma membrane of the presynaptic neuron, with subsequent release of neurotransmitter into the synaptic cleft. 5. Neurotransmitter diffuses across the synaptic cleft and binds to one of two types of postsynaptic receptors. 5a. Neurotransmitter binding to ionotropic receptors causes channel opening and changes the permeability of the postsynaptic membrane to ions. This may also result in a change in the postsynaptic membrane potential. 5b. Neurotransmitter binding to metabotropic receptors on the postsynaptic cell activates intracellular signaling cascades; the example shows G protein activation leading to the formation of cAMP by adenylyl cyclase. In turn, such a signaling cascade can activate other ion-selective channels (not shown). 6. Signal termination is accomplished by removal of transmitter from the synaptic cleft. 6a. Transmitter can be degraded by enzymes (E) in the synaptic cleft. 6b. Alternatively, transmitter can be recycled into the presynaptic cell by reuptake transporters. 7. Signal termination can also be accomplished by enzymes (such as phosphodiesterase) that degrade postsynaptic intracellular signaling molecules (such as cAMP).

Synthesis-storage-inactivation of ACh
After the release of ACh and its interaction with its receptors, it is hydrolyzed by acetylcholinesterase (AChE) to acetate and choline; the latter is taken back up into the nerve terminal and is reused for ACh synthesis. The acetyl CoA was donated by the Mitochondria. Choline +AcetylCoA become Ach via acetylcholine transferase. There are massive amounts of Mito at the terminal.

Synthesis, Storage and Inactivation of NE
The action of NE is terminated by neuronal reuptake into the nerve terminal NE may be inactivated by monoamine oxidase (MAO) w/i the nerve terminal or catechol-O-methyltransferase (COMT) extraneuronally The rate limiting step is Tyr DOPA via tryosine hydroxylase COMT is also in the brain and glial cells but is extraneuronal You can’t give NE in mouth and it must be peripheral b/c it will break down if given orally. MOA COMT

Receptors Acetylcholine receptors  muscarinic or nicotinic (none to blood vessels except certain glands**) Muscarinic – parasympathetic neuroeffector junctions (G-protein coupled, metabotropic) Sweat glands use M2, M3 receptors Odds are G (alphaq, get constriction in smooth muscles) and evens are G (i, inhibit adenylate cyclase and get constriction) M2- heart, respiratory, brain, inhibition of NE (heteroreceptor) and Ach (autoreceptor) M3- eye, stomach (sphincter relaxation, secretion stimulation), bronchoconstriction, vasodilation, emesis, GI (sphincter relaxation, increase sectretion), urinary bladder, pancreas secretion, salivary gland blood vessels, these increase the blood to the gland to get increase in section and this is ONLY area where blood vessels have PARA that cause vasodilation!!! Nicotinic – all autonomic ganglia, somatic neuromuscular junctions & brain [+sympathetic in the adrenal medulla]

Adrenoceptors  α and β α1: contraction of vascular smooth muscle (vasoconstriction), the iris dilator muscle (mydriasis), and urinary tract smooth muscle, increased peripheral resistance Found in vascular smooth muscle, Also found in exocrine glands and the CNS α2: mediate smooth muscle relaxation by feedback inhibition of norepinephrine and Ach release from nerve terminals [decrease outflow of NE] (ex. nasal decongestants work on this in the nose to constrict), prejunctional , inhibit insulin release Also found in platelets and the pancreas β1: cardiac stimulation  positive chronotropic ( HR), ionotropic ( contractility) & dromotropic ( conduction velocity) effects, increase in lipolysis Found in the heart; Activation also increases renin secretion in the kidney β2: mediate relaxation of bronchial (use these for asthma patients), uterine and vascular smooth muscle (vasodilation) Skeletal muscle: mediate K+ uptake Liver: mediate glycogenolysis (increase in muscle and liver, increase blood sugar) β3: enhances lipolysis N.E.D mnemonic for catecholamines: norepinephrine, epinephrine, dopamine

Adrenoceptors  α and β

Domamine receptors  D1: mediate relaxation in vascular smooth muscle
D2: modulate neurotransmitter release Imidazoline receptors: natriuresis (eliminating Na+ in urine causes diuresis and water to follow Na+) and decrease in sympathetic outflow from the CNS (used for the eye and to regulate the enteric NS)  these decrease sympathetics

“Rest and Digest” Slows heart rate Promotes digestion, defecation, & mic- Turition CNX- not sure of Para functin in the kidney so consider it null; visceral organs, parotid CNIII- ciliary m. and lacrimal gland CN VII, IX- to salivary gland, sublingual and submandibular gland “Fight or Flight” Cardiovascular stimulation Skeletal muscle activation Glycogenolysis Lipolysis

Mucal secretions of the salivary glands is regulated by beta receptors

How DO I Remember All of This
Remember the parasympathetic DUMBBELLS Diarrhea Urination Miosis Bradycardia Bronchoconstriction, Bronchospasm Erection (Excite skeletal muscle, Emesis) Lacrimation Lethargy Salivation and Sweating .

The Baroreceptor Reflex

Brody’s Human Pharmacology 5th ed.

Storage and Release of Acetylcholine
Drugs acting at each step of Synaptic Transmission Hemicholinium- block choline uptake Tetrodotoxin- blocking AP Na+ channels α-Latrotoxin*- form pores in lipid membranes induce Ca2+ inflow (from black widow spider) Botulinium toxin- - blocks synaptobrevin preventing vesicle fusion Atropine- muscarinic receptor antagonist Physostigmine- ACHE inhibitor Dantrolene- blocks ryanodine receptor which are major mediators of intracellular Ca2+ release Depolarization leads to Ca entry leads to vesicle fusion 1a.Hemicholinium-blocks choline uptake, no clinical use 1b.Vesamicol-blocks ach uptake into vesicles, no clinical use 2. TTX blocks voltage-gated fast Na channels preventing action potentials (pufferfish) 3.Alpha latrotoxin Instead, the toxin can form pores in the lipid membranes and induce Ca2+ ionflow. LEMS=lambert eaton myasthenic syndrome, black widow spider 4. Botulinum toxin, degrades synaptobrevin preventing vesicle fusion 5. Muscarinic receptor antagonist (atropine) 6. Acetylcholinesterase inhibitor (physostigmine) 7. Activation of nicotinic receptors can cause an action potential opening voltage-dependent calcium channels. Dantrolene blocks ryanodine receptor which are the major mediator of intracellular calcium induced calcium release (muscle contraction)

Do Hemicholinium and Vesamicol have a Clinical Use?
No, because they are nonselective cholinergic antagonist causing complete depletion and inactivation of all cholinergic systems. Trimethaphan can be used for an Aoritic dissection, to lower blood pressure and block the sympathetic response

Nicotinic Receptor Agonists
Nicotine – prototype Activates sympathetic (vascular system) & parasympathetic ganglia (GI tract)  blood pressure & heart rate Diarrhea & urination Crosses BBB  alertness, vomiting, tremors, convulsions and coma

Nicotinic Receptor Agonists
Varenicline (Chantix) – partial agonist in the brain Indicated for smoking cessation Reduces craving and withdrawal effects BUT Associated with suicidal ideation, depression, changes in behavior

Muscarinic Receptor Agonists
M1 - M5 Activate parasympathetic nerves Constriction of iris (miosis) Contraction of ciliary muscle Constriction of airways Increase in GI motility Contraction of bladder and relaxation of its outlet Decrease in heart rate Increased secretions (sweat, saliva, lacrimal, etc.)

Muscarinic Receptor Agonists
Bethanecol (Urecholine) Stimulates bladder and GI w/o affecting HR or BP Indicated for postoperative ileus, urinary retention Pilocarpine Lowers intraocular pressure by increasing outflow of aqueous humor (glaucoma) Stimulates salivary gland secretion (xerostomia) Cevimeline (Evoxac) Stimulates salivary gland secretion (xerostomia) Indicated in patients with Sjögren's syndrome Side effects – extension of the parasympathomimetic actions If given in high doses or parenterally, acute circulatory failure & cardiac arrest CI: asthma, COPD, PUD

‘Shrooms Mushrooms - Inocybe and Clitocybe contain muscarine
Amanita muscaria Mushrooms - Inocybe and Clitocybe contain muscarine Diarrhea, sweating, salivation and lacrimation No current medicinal use Edibility: Toxic Clitocybe dealbata Clitocybe rivulosa Inocybe erubescens

Heterotrimeric G proteins involved in the regulation of smooth muscle tone. Gq/G11-coupled receptors increase the intracellular Ca2+ concentration, leading to Ca2+/calmodulin (CaM)-dependent MLCK activation and MLC20 phosphorylation. Especially G12/G13-coupled receptors mediate RhoA activation, thereby contributing to Ca2+-independent smooth muscle contraction. Relaxation is induced by activation of Gs-coupled receptors, but the mechanisms underlying cAMP-mediated relaxation are not clear. Gi-mediated signaling might contribute to contraction by inhibiting Gs-mediated relaxation. cGKI, cGMP-dependent protein kinase I; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; MLC20, regulatory chain of myosin II; MLCK, myosin light-chain kinase; MPP, myosin phosphatase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, cAMP-dependent kinase; PLC-β, phospholipase C-β; RhoGEF, Rho specific guanine nucleotide exchange factor; ROCK, Rho kinase; TRP, transient receptor potential channel.

Acetylcholinesterase (AChE)
Removes ACh from the synapse by degradation to choline + acetate Terminates neurotransmission at cholinergic synapses Time required is less than 1 millisecond

Cholinesterase Inhibitors
Reversible – short-acting Noncovalent – bind to the anionic domain of AChE, rapid hydrolysis Covalent – also bind to AChE, but form a carbamoylated enzyme that undergoes slow hydrolysis Edrophonium – used in diagnosis of myasthenia gravis Neo- and pyridostigmine – myasthenia gravis, reversal of neuromuscular blockade, postoperative urinary retention Physostigmine - glaucoma Donepezil, galantamine, rivastigmine – Alzheimer’s disease

Myasthenia Gravis – “Grave muscle weakness”
Autoimmune disease Autoantibodies against the nicotinic cholinergic receptor at the NM junction  reduced numbers of receptors  skeletal muscle weakness Symptoms: drooping of one or both eyelids (ptosis), double vision (diplopia); altered speech, difficulty swallowing, problems chewing, loss of facial expressions Muscle weakness increases during activity and improves after rest

Myasthenia Gravis: Diagnosis
AChE inhibitors amplify the effects of ACh, temporarily restoring muscle strength Edrophonium – blocks ACh hydrolysis Rapid but brief improvement in strength after IV administration Fasciculation (muscle twitch) generally occurs if NOT Myasthenia Also used in myasthenic crisis

Myasthenia Gravis: Treatment
Pyridostigmine (Mestinon) taken orally every day Dose may vary on day to day basis (stress, infection, etc.) Immune suppressants given concomitantly (corticosteroids) AEs: abdominal cramping, diarrhea

Cholinesterase Inhibitors
Irreversible – long-acting Phosphorylate AChE – strong bond, very slow hydrolysis Organophosphates – pesticides and nerve gases Highly lipid-soluble and absorbed from skin, mucous membranes and gut Activate both muscarinic and nicotinic receptors Therapeutic uses Echothiophate - glaucoma Malathion (Ovide) – pediculosis capitis; kills ova and adult lice

Organophosphate Poisoning
Toxic nerve gases – sarin, soman, tabun and VX Insecticides – parathion and malathion Agriculture major source of intoxications Time to death - 5 min to 24 h if untreated, depending on route of exposure Symptoms Initial - miosis, salivation, sweating, bronchoconstriction, vomiting, diarrhea CNS – cognitive disturbance, seizure, coma Neuromuscular blockade Treatment: 1) supportive care (airway), 2) decontamination, 3) atropine (large doses), 4) benzodiazepines (for seizures), 5) pralidoxime [2-PAM] (regenerates ChE)

Cholinergic Transmission
Drugs that enhance cholinergic transmission: Nicotinic receptor agonists, e.g., nicotine Muscarinic receptor agonists, e.g., bethanechol Cholinesterase inhibitor, e.g., physostigmine Drugs that inhibit cholinergic transmission: Inhibitors of vesicular ACh transport , e.g., vesamicol Inhibitors of exocytotic release, e.g., botulinum toxin Nicotinic receptor antagonists Muscarinic receptor antagonists (e.g., atropine) Inhibitors of high-affinity choline transport, e.g., hemicholinium Inhibitors of pyruvate dehydrogenase, e.g., bromopyruvate

Nicotinic receptor antagonists
Ganglionic blocking drugs – block nicotinic receptors on postjunctional neurons in sympathetic and parasympathetic ganglia Effect depends on which is dominant: Sympathetic – hypotension Parasympathetic – dry mouth, blurred vision & urinary retention Not used clinically

Role of Cholinergic Receptors of the Autonomic Ganglia
Copyright © 2012 McGraw Hill Medical Post synaptic potentials recorded form an autonomic postganglionic nerve cell body after stimulation of the preganglionic nerve fiber. The preganglionic nerve releases ACh onto postganglionic cells. The initial EPSP (excitatory postsynaptic potential) results from the inward Na+ current (and perhaps Ca2+ current) through the nicotinic receptor channel. If the EPSP is of sufficient magnitude, it triggers an action potential spike, which is followed by a slow IPSP (inhibitory post, a slow EPSP, and a late, slow EPSP. The slow IPSP and slow EPSP are not seen in all ganglia. The electrical events subsequent to the initial EPSP are thought to modulate the probability that a subsequent EPSP will reach the threshold for triggering a spike. Other interneurons, such as catecholamine-containing, small, intensely fluorescent (SIF) cells, and axon terminals from sensory, afferent neurons also release transmitters and that may influence the slow potentials of the postganglionic neuron. A number of cholinergic peptidergic, adrenergic, and amino acid receptors are found on the dendrites and soma of the postganglionic neuron and the interneurons. The preganglionic fiber releases ACh and peptides: the interneurons store and release catecholamines, amino acids, and peptides: the sensory afferent nerve terminals release peptides. The initial EPSP is mediated through nicotinic (Nn) receptors, the slow IPSP and EPSP through M2 and M1 muscarinic receptors, and the late, slow EPSP through several types of peptidergic receptors. Ipsp in some neurons is the result of ACh stimulated release of catecholamines (dopamine and norepinephrine) from SIF cells that hyperpolarize the postsynaptic cell causing an IPSP Peptides involved with the late slow epsp include Gonadotropin-releasing hormone Substance P Angiotensin Calcitonin gene-related peptide Vasoactive intestinal polypeptide nPY Enkephalins And others can be modulated by 5HT gaba

PARASYMPATHETIC → SYMPATHETIC →

Predominant Autonomic Tone and The Consequences of Autonomic Ganglionic Blockade
SITE PREDOMINANT TONE EFFECT OF GANGLIONIC BLOCKADE Arterioles Sympathetic-adrenergic Vasodilation, hypotension Veins Dilation, peripheral pooling Heart Parasympathetic-ACh Tachycardia Iris Mydriasis Ciliary Cycloplegia GI Reduced tone & secretions Urinary Urinary retention Salivary Xerostomia Sweat Sympathetic-ACh Anhidrosis Genital Sympathetic & Para- Decreased stimulation Site/predominant tone/effect Arterioles/S/vasodilation;increased peripheral blood flow;hypotension Veins/S/dilation;peripheral pooling;decreased venous return;decreased cardiac output Heart/P/tachycardia? Very tone dependent was heart rate already high or low Iris/P/Mydriasis Ciliary muscle/P/Cycloplegia-focus on far vision Gastrointestinal tract/P/Reduced motility;constipation;decrease gastric and pancreatic secretions (except B cells which are under sympathetic tone and the effect will increase insulin) Urinary bladder/P/Urinary retention (loss of contraction of the detrusor muscle in the bladder, bladder relaxes) Salivary glands/P/xerostomia Sweat glands/S/anhidrosis (a receptors in the hands and soles of feat (stress sweating), while body is under M3,M2 receptor control (heat sweating)) Genital tract/Both/impotence;ED

Hexamethonium Man W. D. M. Paton, Pharm. Rev. 6, 59 (1954)
He is a pink complexioned person, except when he has stood for a long time, when he may get pale and faint. His handshake is warm and dry. He is a placid and relaxed companion; for instance he may laugh, but he can’t cry because the tears cannot come. Your rudest story will not make him blush, and the most unpleasant circumstances will fail to make him pale. His socks and his collars stay very clean and sweet. He wears corsets and may, if you meet him out, be rather fidgety (corsets to compress his splanchnic vascular pool, fidgety to keep the venous return going from his legs). He dislikes speaking much unless helped with something to moisten his dry mouth and throat. He is long-sighted and easily blinded by bright light. The redness of his eyeballs may suggest irregular habits and in fact his head is rather weak. But he always behaves like a gentlemen and never belches or hiccups. He tends to get cold and keeps well wrapped up. But his health is good; he does not have chilblains and those diseases of modern civilization, hypertension and peptic ulcers, pass him by. He is thin because his appetite is modest; he never feels hunger pains and his stomach never rumbles. He gets rather constipated so his intake of liquid paraffin is high. As old age comes on he will suffer from retention of urine and impotence, but frequency, percipitancy, and strangury will not worry him. One is uncertain how he will end, but perhaps if he is not careful, by eating less and less and getting colder and colder, he will sink into a symptomless, hypoglycemic coma and die, as was proposed for the universe, a sort of entropy death. W. D. M. Paton, Pharm. Rev. 6, 59 (1954)

Discussion and Questions?
Is hexamethonium used to treat anything? No, however, trimethaphan and mecamylamine were the first anti-hypertensive agents ever used. They were developed and used during the Today, trimethaphan can be used to treat aortic dissection, to lower blood pressure and block sympathetic response while mecamylamine is an orphan drug for Tourette’s syndrome Is this how cigarettes work? Nicotine’s effects are a summation of its effects on sympathetic and parasympathetic systems Includes autonomic ganglia stimulation and depolarization block Includes stimulatory effects on carotid and aortic chemoreceptors (blocked by hex), it effects all sorts of sensory and chemo receptors including the CTZ, vomiting) Includes its effect on of epi release from the adrenal medulla Biphasic, transient stimulation followed by persistent depression Very high doses, non-recreational doses, can cause paralysis CNS stimulation Primary site of action is prejunctional causing neurotransmitter release. Increase excitatory amino acids leads to stimulatory action Increase dopamine leads to the addiction and pleasure Long term use causes increase receptor density contributing to tolerance and dependence

Discussion and Questions?
Is hexamethonium used to treat anything? Is this how cigarettes work? Nicotine’s effects are a summation of its effects on sympathetic and parasympathetic systems. This includes autonomic ganglia stimulation followed by a depolarization block. It also effects sensory and chemo receptors including the CTZ causing vomiting. It has the same biphasic effect on epinephrine release from the adrenal medulla. It causes CNS stimulation primarily at prejunctional nerve terminals causing neurotransmitter release. This includes excitatory amino acids, leading to it’s stimulatory action, and dopamine which leads to the addiction and pleasure. Nicotine’s effects are a summation of its effects on sympathetic and parasympathetic systems Includes autonomic ganglia stimulation and depolarization block Includes stimulatory effects on carotid and aortic chemoreceptors (blocked by hex), it effects all sorts of sensory and chemo receptors including the CTZ, vomiting) Includes its effect on of epi release from the adrenal medulla Biphasic, transient stimulation followed by persistent depression Very high doses, non-recreational doses, can cause paralysis CNS stimulation Primary site of action is prejunctional causing neurotransmitter release. Increase excitatory amino acids leads to stimulatory action Increase dopamine leads to the addiction and pleasure Long term use causes increase receptor density contributing to tolerance and dependence

Nicotinic Receptor Antagonists
Neuromuscular blocking drugs - bind to muscle nicotinic receptors and inhibit ACh neurotransmission at skeletal neuromuscular junctions  muscle weakness and paralysis Remember this for later

Muscarinic Receptor Antagonists
Competitive antagonists: compete with ACh at parasympathetic neuroeffector junctions  inhibit parasympathetic nerve stimulation AKA parasympatholytics Relax smooth muscle, increase heart rate, inhibit exocrine gland secretion Generally not selective for different receptor subtypes

Muscarinic Receptor Antagonists
Belladonna alkaloids Atropine Hyoscyamine Scopolamine Semisynthetic/synthetic agents Dicyclomine Glycopyrrolate Ipratropium Oxybutynin etc…

Case A 16-year-old male was brought to the ER by friends after becoming highly agitated and experiencing visual hallucinations, claiming that one of his friends had a mailbox for a head He ingested some seeds from plants growing in a vacant lot; denied EtOH or other substances PE: Dry skin and mucous membranes, absent bowel sounds, sinus tachycardia, dilated pupils & blurred vision Labs: WNL; EtOH - 0

Case Gastric lavage was performed & activated charcoal was administered to remove any unabsorbed substances The patient became more agitated and delusional An infusion of physostigmine was administered x 2 His symptoms began to subside and 12 hours later he was much improved 36 hours later he was discharged with normal vital signs and mental status The plant material was identified as Datura stramonium

Anticholinergic Toxicity
Jimson weed or locoweed (Datura stramonium) Hallucinogenic plant containing belladonna alkaloids found throughout the U.S. Toxic via ingestion or inhalation Fatalities have occurred Treatment Remove drug (plant material) from GI tract Supportive care Cholinesterase inhibitor (physostigmine);  ACh & counteracts central nervous system toxicity (hallucinations, seizures)

Belladonna alkaloids Atropa belladonna (deadly nightshade)
Datura stramonium (Jimson weed) Hyoscyamus niger Belladonna – “fair lady”, referred to pupil dilation produced by extracts of these plants; considered attractive during the Renaissance Atropine – Hyoscyamine - Scopolamine

Atropine/Scopolamine/Hyoscyamine
Well absorbed Tertiary amines so distribute in to the CNS Excreted via urine; t1/2 ~ 2 hours Ocular t1/2 is longer; bind to iris pigmentation, pigments slowly release drug over days; darker irises bind more Toxicity: Dry as a bone, blind as a bat, red as a beet and mad as a hatter

Atropine/Scopolamine/Hyoscyamine
Ocular: Mydriasis Cycloplegia Dry eyes Respiratory: Dilation  secretions CNS: Sedation OR stimulation Delirium GI/Urinary: LES – reflux Motility Gastric acid secretion Urinary retention Cardiac: HR (standard dose)  HR (low dose) Misc: Sweating  hyperthermia

Can’t see Can’t pee Can’t spit Can’t s*%t

Atropine, et al: Indications
Ocular: Mydriasis – ophthalmoscopic exam Cycloplegia – refractive errors of lens Iritis, cyclitis Respiratory: Palliative care – decrease respiratory secretions GI/Urinary: Motility – intestinal/urinary spasm & pain (hyoscyamine) CNS: Motion sickness (scopolamine) - blocks ACh from vestibular to vomiting center Parkinson’s disease Misc: SEs of myasthenia gravis treatment Reverse cholinesterase inhibitor overdose Cardiac: HR– sinus bradycardia (IV)

Semisynthetic/Synthetic Agents
Pharmacologic effects similar to atropine-like agents but pharmacokinetic profiles make them useful in specific situations Ipratropium/tiotropium – administered via inhalation; few systemic side effects; COPD Dicyclomine – symptoms of irritable bowel: intestinal cramping Oxybutynin, darifenacin, solifenacin, fesoterodine, tolterodine, trospium – overactive bladder (frequency, nocturia, urgency, incontinence)

Semisynthetic/Synthetic Agents
Glycopyrrolate Preoperatively to inhibit secretions of salivary and respiratory tract During anesthesia to inhibit secretory and vagal effects of cholinesterase inhibitors used to reverse neuromuscular blockade Manage oral secretions in terminally ill patients Tropicamide – mydriatic for eye exam; short duration of action (~ 1 hour)

Muscarinic Receptor Antagonist Contraindications
Ophthalmic preps in elderly & those with narrow angles – can trigger acute angle-closure glaucoma Bowel atony Urinary retention Prostatic hypertrophy Co-administration with other anticholinergic agents

Ocular Effects of Muscarinic Drugs
A: Relationship between the iris sphincter and ciliary muscle in the normal eye. B: Effects of pilocarpine, a muscarinic receptor agonist: pupillary constriction (miosis), contraction of the ciliary muscle, relaxation of the suspensory ligaments connected to the lens, increase in lens thickness. As the lens thickens, its refractive power increases so that it focuses on close objects. C: Effects of atropine, a muscarinic receptor antagonist: pupillary dilation (mydriasis), increased tension on suspensory ligaments, lens becomes thinner & focuses on distant objects.

* *Do not penetrate BBB very well - fewer CNS side effects
Brody’s Human Pharmacology 5th ed.

Review Questions The major neurotransmitter in the parasympathetic nervous system is _________, while the major neurotransmitter in the sympathetic nervous system is ________. Acetylcholine and norepinephrine Norepinephrine and acetylcholine

Review Questions Reversible cholinesterase inhibitor
Irreversible cholinesterase inhibitor Malathion Edrophonium Physostigmine Donepezil Echothiophate

Review Questions Which of the following are effects of muscarinic receptor activation? Decrease in heart rate Increase in heart rate Decrease in GI motility Secretion of hydrochloric acid Bronchodilation

Review Questions A patient presents with confusion, blurred vision, dry mouth and constipation. These are symptoms of: Anticholinergic toxicity Cholinergic toxicity Myasthenia gravis Organophosphate poisoning

Lecture 3, 4, 5 Autonomic Pharmacology
Explain the function and mechanism of action of all elements of the ANS Define the roles of cholinergic and adrenergic receptors, their differences, and systemic responses Differentiate between the actions of muscarinic, nicotinic and adrenergic receptors and their subtypes Identify and explain the mechanism of action for pharmacological agents used to manipulate these systems, and their role in pharmacotherapy Define the pharmacologic rationale for therapeutic application of autonomic-acting agents Given a generic drug name, define mechanism of action, side effects, and therapeutic utility

Noradrenergic transmission
Drugs that enhance or mimic noradrenergic transmission (sympathomimetics): Facilitate release, e.g., amphetamine Block reuptake, e.g., cocaine Receptor agonists, e.g., phenylephrine Drugs that reduce noradrenergic transmission (sympatholytics): Inhibit synthesis, e.g., 4a, α-methyltyrosine; 4b, carbidopa; 4c, disulfiram Disrupt vesicular transport and storage, e.g., reserpine Inhibit release, e.g., guanethidine Receptor antagonists, e.g., phentolamine Methyltyrosine adds a methyl to Tyr so it can’t become L-Dopa and carbidopa adds a carb to L-DOPA so it can’t become dopamine and disulfiram ads a sulfure to dopamine to it can’t become NE. Then the reserpine blocks the storage of pine trees and the guanethidine blocks release and phentolamine is the toll that binds to the receptor. Amphtamine for the release, cocaine for he reuptake, and phenylephrine is the receptors friend.

3 Classes of: Adrenoreceptor agonists
Direct-acting: bind to and activate the receptors Catecholamines & noncatecholamines Indirect-acting: increase the concentration of norepinephrine at neuroeffector junctions Mixed-acting: direct & indirect actions

Direct-acting agonists: Catecholamines
Naturally occurring Synthetic Norepinephrine Epinephrine Dopamine Isoproterenol Dobutamine Rapidly inactivated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in the gut, liver, & other tissues Catecholamine basic structure must have –OH at 3 and 4 or lose activity Low bioavailability, short half-life = parenteral administration required

Direct-acting agonists: Catecholamines
NE: α1= α2 , β1> β2 Activation of α1 receptors = vasoconstriction,  peripheral resistance;  systolic & diastolic blood pressure  reflex bradycardia EPI: α1= α2 , β1= β2 Low dose: β2 receptor stimulation = vasodilation,  DBP; bronchodilation High dose: α1 stimulation = vasoconstriction,  SBP & DBP Isoproterenol: β1= β2 >>>α Activation of β1& β2 = cardiac stimulation & vasodilation;  DBP but  SBP by increasing heart rate & contractility; potent chronotropic effect may lead to tachycardia and tachyarrhythmias; bronchodilation Dopamine: D1> β1 >α Low dose: D1 = renal vasodilation; Mid dose: β1 =  cardiac contractility, cardiac output, tissue perfusion; High dose: α1 receptors = vasoconstriction Dobutamine: β1> β2 >α β1 =  cardiac contractility, cardiac output; β2 = vasodilation,  vascular resistance SBP = systolic blood pressure; DBP = diastolic blood pressure

Mean Arterial Pressure
Perfusion pressure seen by organs in the body Want MAP > 60 mmHg is enough to sustain the organs of the average person (70 to 110 mmHg) If the MAP falls significantly below this number for an appreciable time, the end organ will not get enough blood flow, and will become ischemic MAP = 1/3(SBP-DBP)+DBP

Catecholamines: Indications
Shock Cardiogenic Neurogenic & Septic Anaphylactic Cardiac arrest (Epi) Bradycardia/AV block (Iso) Prolongation of local anesthetic action (Epi) Acute heart failure (Dobu) Note: Catecholamines that increase blood pressure are also called vasopressors

Shock Profoundly decreased blood flow to vital organs
Hypovolemic: inadequate blood volume; tx by giving fluid saline Cardiogenic: inadequate heart function; called cold shock Neurogenic/septic: inadequate vasomotor tone Septic: pathogenic microorganisms produce toxins causing massive vasodilation; called warm shock Anaphylactic: severe immediate hypersensitivity reaction with hypotension and difficulty breathing

Shock: General principles
Fluid resuscitation if hypovolemic Cardiogenic shock: 1) dobutamine, 2) dopamine Neurogenic/septic shock: norepinephrine; often in combination with dopamine to preserve renal blood flow; goal MAP > 60 mm Hg Anaphylactic shock: epinephrine

Catecholamines: Adverse effects
Excessive vasoconstriction Tissue ischemia/necrosis Reduction of blood flow to vital organs Excessive cardiac stimulation Arrhythmias Glycogenolysis (β2) Hyperglycemia

Longer duration of action
Non-catecholamines Do not contain a catechol moiety Not substrates for COMT May be resistant to degradation by MAO Effective orally Longer duration of action

Phenylephrine (the friend of the receptor)
Well absorbed orally and topically; may also be given IV Partly metabolized by MAO in the liver and intestine Activates α1 receptors

Phenylephrine: Indications
Viral/allergic rhinitis: nasal decongestant Allergic conjunctivitis: ocular decongestant Mydriasis: ophthalmologic exam Hypotension/shock due to: Excessive vasodilators Drug-induced Septic shock Neurogenic shock Maintenance of BP during surgery (anesthesia-induced hypotension)

Midodrine Rapidly absorbed after oral administration
Metabolized in the liver/tissues to active metabolite (desglymidodrine) Activates α1 receptors = vasoconstriction, SBP & DBP while standing, sitting & supine Indicated to treat postural (orthostatic) hypotension when non-pharmacologic treatment fails AE: Hypertension, especially when supine

β2 agonists Selective β2 agonists, however, at higher doses may stimulate β1 receptors as well Bioavailability 30-50% (incomplete absorption, 1st-pass metabolism) Metabolized to inactive compounds; renally excreted PO, IV or via inhalation

β2 agonists: Indications
β2: relaxation of bronchial, uterine and vascular smooth muscle Obstructive lung disease: asthma, COPD Premature labor AEs: tachycardia, skeletal muscle tremor, nervousness Albuterol Metaproterenol Salmeterol Formoterol Bitolterol Ritodrine Terbutaline- relaxes uterine muscles More on these in the Cardio-Pulmonary Block!

Imidazolines α1 receptor activation: oxymetazoline (non-selective α-adrenergic agonist) Nasal & ocular decongestant α2 receptor activation: apraclonidine, brimonidine  intraocular pressure with ocular surgery –”onidines” α2- & imidazoline- receptor activation in the CNS Clonidine – hypertension Dexmedetomidine – sedation during mechanical ventilation

Clonidine α 2-receptor agonist in the CNS (medulla)  reduced sympathetic outflow  peripheral resistance, heart rate, and cardiac output =  BP AEs: dry mouth, sedation, dizziness Abrupt withdrawal = sympathetic NS over activity (HTN, tachycardia & sweating); “rebound HTN” Guanabenz & guanfacine

Indirect acting agonists
Amphetamine Inhibits the storage of norepi by neuronal vesicles  reverse transport back into the synapse Highly lipid soluble Increases norepi in the CNS & peripherally Vasoconstriction, cardiac stimulation,  BP and CNS stimulation Cocaine Blocks neuronal uptake of norepi at central and peripheral synapses  stimulates the sympathetic NS Vasoconstriction, pupillary dilation, cardiac stimulation,  BP and CNS stimulation  cardiac damage/heart failure Local anesthetic

Mixed-acting agonists
Ephedrine & pseudoephedrine (isomer) Activate α1 receptors  vasoconstriction (nasal decongestants),  BP & urinary retention Activate β1 receptors  tachycardia Activate β2 receptors  bronchodilation CNS stimulation  insomnia

Mixed-acting agonists
Ephedrine derived from a naturally occurring plant, Ephedra, AKA Ma Huang Well absorbed, lipid soluble Relatively resistant to MAO and COMT metabolism = long duration of action Found in dietary supplements until banned by the FDA due to deaths caused by hypertension and cardiac stimulation

Adrenoreceptor antagonists
Reduce sympathetic stimulation; sympatholytics Therapeutic effects Blocking α1 receptors = vascular & smooth muscle relaxation Blocking β1 receptors = reduces sympathetic stimulation of the heart Adverse effects Blocking α2 receptors = dizziness, headache, nasal congestion Blocking β2 receptors = bronchoconstriction, inhibits glycogenolysis

Selective α1- antagonists
Vasodilation,  BP; relax the bladder, urethra and prostatic smooth muscle Indications – it is an o-sin to block alpha1 Hypertension (doxazosin, prazosin & terazosin) Urinary symptoms (frequency, urgency & nocturia) due to benign prostatic hypertrophy (alfuzosin, tamsulosin) AEs: hypotension, dizziness, sedation

Selective α1- antagonists
Prazosin – duration of action ~ 6 hours; first-pass metabolism; renal/biliary excretion Doxazosin – duration of action ~ 30 hours Terazosin – duration of action ~ 20 hours Although indicated in the treatment of HTN, not first-line AE: Orthostatic hypotension Alfuzosin/tamsulosin – “uroselective” Relieve lower urinary tract symptoms without as much hypotension, dizziness & sedation

Nonselective α-adrenergic antagonists
Phenoxybenzamine Phentolamine Spontaneous chemical transformation to an active metabolite  stable covalent bond with the α receptor  noncompetitive antagonism of epinephrine & other adrenergic agonists Gradual onset, duration ~ 3-4 days  Vascular resistance,  BP Indication: hypertension in pheochromocytoma until surgery Imidazoline Competitive antagonist Onset immediate (IV), duration min Hepatic metabolism, renal excretion  Vascular resistance,  BP Indications: hypertension caused by α1-agonists; dermal necrosis & ischemia caused by extravasation of epinephrine. Perioperative use for patients with pheochromocytoma.

Selective α2-blockers Yohimbine (Yocon) Neuroleptic Agents
Competitive antagonist, α2 selective Bark of Pausinystalia yohimbe Enters CNS –  BP, HR, motor activity Actions appear opposite that of clonidine Used (herbal treatment) for male sexual dysfunction Neuroleptic Agents Dopamine (D2) receptor antagonists Chlorpromazine, haloperidol, phenothiazines Induce side effects via blockade of α2

Selective β1 - antagonists
β1 > β2 Primarily located in cardiac tissue β1-blockers AKA cardioselective β-blockers However, as dose increases, β2 receptor blockade increases Negative chronotropic, ionotropic and dromotropic effects Decrease cardiac output and BP Decrease aqueous humor secretion in the eye and intraocular pressure

Broncho-constriction
Drug Lipid solubility Bioavailability Half-life Indications Adverse effects Acebutolol Medium 40% 10-12 h HTN Arrhythmias Broncho-constriction Fatigue Depression Bradycardia Sexual dysfunction Atenolol Low 50% 6-7 h HTN, acute MI, angina Betaxolol 90% 14-22 h HTN, HF, Glaucoma Bisoprolol 80% 9-12 h HTN, HF Esmolol 100% (IV) 10 min Acute SVT Metoprolol 3-4 h angina, MI Use for HT  O-lol I am not learning that beta 1 selective antagonist ---

Nonselective β - antagonists
Block β1-receptors in cardiac tissue and β2-receptors in smooth muscle, liver, & other tissues Intrinsic sympathomimetic activity Membrane-stabilizing activity Inhibit epinephrine-stimulated glycogenolysis Mask signs of early hypoglycemia (sweating, tachycardia)

Intrinsic sympathomimetic activity ISA
Partial agonist activity = smaller reduction in heart rate when the patient is resting and sympathetic tone is low Pindolol (non-selective) and acebutolol (selective)

Membrane-stabilizing activity
Local anesthetic activity Block sodium channels cardiac nerves = slow conduction velocity, perhaps contributing to antiarrhythmic effects Pindolol and propranolol (nonselective)

HTN, angina, migraine HA prophylaxis Broncho-constriction
Drug Lipid solubility Bioavailability Half-life Indications Adverse effects nadolol Low 35% 15-20 h HTN, angina, migraine HA prophylaxis Broncho-constriction Fatigue Depression Bradycardia Sexual dysfunction pindolol Medium 75% 3-4 h HTN Propranolol- 1st drug discovered High 25% 4-6 h HTN, angina, essential tremor, migraine HA prophylaxis timolol 50% HTN, migraine HA prophylaxis, glaucoma

α- and β-antagonists- go to the lab to carve out receptors lol
Drug MOA F Half- Life Effects Indications Carvedilol β1 & β2-blocker; α1- blocker 30% 6-8 h Vasodilation,  HR & BP,  CO HTN Heart Failure Labetalol 20% Vasodilation,  HR & BP

Review questions Activation of β1 receptors produces cardiac stimulation while activation of β2 receptors mediates smooth muscle relaxation.

Review questions Which of the following receptors are associated with renal vasodilation when activated? α1 β1 D1 Which catecholamine has this effect? dopamine

Review questions Catecholamine Z is injected. The patient’s BP and peripheral resistance rises; the HR decreases. Which catecholamine was given? Dopamine Epinephrine Isoproterenol Norepinephrine

Review questions Doxazosin Metoprolol Phenoxybenzamine Tamsulosin
A new patient of yours with episodic severe HTN is found to have markedly elevated levels of epinephrine and norepinephrine metabolites in his urine. What would you prescribe to lower his blood pressure before surgery? Doxazosin Metoprolol Phenoxybenzamine Tamsulosin

Lecture 6 Neuromuscular Blocking Agents
Define the mechanism of action of neuromuscular blocking agents and know their indications Relate pharmacokinetic parameters to drug selection Convey information related to drug interactions and side effects Explain the pharmacological rationale behind use of these drugs in clinical settings

History In the 16th century, European explorers found that South American natives in the Amazon basin were using an arrow poison, curare, to produce skeletal muscle paralysis in the animals they were hunting Active compound – d-tubocurarine

Nicotinic Receptors N1 or NM and N2 or NN Ligand-gated ion channel
ε N1 or NM and N2 or NN Ligand-gated ion channel Requires binding of two acetylcholine molecules Composed of five subunits (pentamer) Five different types of subunits α, β, γ, δ and ε 10 different α and 4 different β subunits NM receptors contain only α1 and β1 subtypes plus δ and γ/ε NN receptors contain α2-10 and β2-4 subtypes

Neuromuscular blocking agents
Introduced in the 1940s Structural analogs of acetylcholine (ACh) MOA: Bind to the nicotinic acetylcholine receptor at the motor end plate and inhibit binding of ACh at skeletal neuromuscular junctions  muscle weakness and paralysis Do not cross the blood-brain barrier, thus a patient may be paralyzed but completely aware Classified as either depolarizing or nondepolarizing

Classification Depolarizing agents Nondepolarizing agents Occupy and activate the nicotinic receptor for a prolonged period of time, leading to blockade: nicotinic receptor agonists Structures resemble that of acetylcholine (ACh) Competitively antagonize the actions of ACh at the nicotinic receptor Majority of agents fall into this classification

Peripheral Nerve Stimulator
Contraction of the adductor pollicis muscle Determine Type Onset Magnitude Duration ED95 95% suppression on a single twitch Used to quantify the potency of a neuromuscular blocker

Other pharmacologic actions
Stimulate the release of histamine  bronchospasm & hypotension (tubocurarine, mivacurium and atracurium) Block autonomic ganglia  hypotension & tachycardia (tubocurarine) Block cardiac muscarinic receptors  tachycardia (pancuronium)

Pharmacokinetics Poor absorption from GI tract; only administered by intravenous route Do not enter cells or cross blood-brain barrier; distribution volume is similar to blood volume Eliminated in urine and bile primarily as unchanged compounds, some as hepatic metabolites Atracurium & cisatracurium (a stereoisomer of atracurium) undergo spontaneous nonenzymatic degradation (Hofmann elimination); preferred for patients with impaired liver and kidney function

Drug Histamine release Ganglionic blockade Onset of action (min) Duration of action (min) Elimination Succinylcholine*depolarizing Minimal None 1.5 Short (5-10) Plasma cholinesterase Atracurium Varies Low 3 Intermediate (30-60) Plasma esterase Cisatracurium Spontaneous degradation Pancuronium Medium Long (60-120) Renal Rocuronium 1 Biliary/renal Tubocurarine High 2 Renal/biliary Vecuronium Hepatic metabolism

Succinylcholine Persistent depolarization of the motor end plate due to lack of metabolism by Acetylcholinesterase (AChE) Phase I block – initial muscle fasciculations over the chest and abdomen  flaccid paralysis of eye and face muscles, arms, legs and neck muscles, then intercostal muscles and diaphragm Phase II block – membrane repolarizes but is still unresponsive; desensitized nicotinic receptor Recovery occurs in reverse order: diaphragm regains function first, followed by limb and trunk muscles, and lastly small muscles

Succinylcholine MOA

Phase II - desensitizing
Phase I – depolarizing Phase II - desensitizing These effects cannot be reversed by cholinesterase inhibitors

Succinylcholine: Adverse effects
Genetic variations in butyrylcholinesterase activity  either 1) lower concentrations of the enzyme or 2) an abnormal enzyme resulting in a longer duration of activity and apnea May cause increased intraocular pressure and intragastric pressure Hyperkalemia ( K+) patients with burns, neuromuscular disease or nerve damage, closed head injury and other trauma may release potassium into the blood, rarely resulting in cardiac arrest

Indications of NM Blockers
Endotracheal intubation  muscle contractility, decreasing the depth of anesthesia required for surgery In patients on mechanical ventilation (ICU) to decrease O2 consumption and prevent high airway pressures if sedation alone is not enough Prevent bone fractures during electroconvulsive therapy

Drug interactions Inhaled anesthetics potentiate neuromuscular blockade Isoflurane Sevoflurane Desflurane Enflurane Halothane Nitrous oxide Dose must be reduced when used together Malignant hyperthermia: rare interaction with succinylcholine; abnormal release of calcium from skeletal muscle causes muscular contraction, rigidity and heat production; hyperthermia, metabolic acidosis, tachycardia

Drug interactions Antibiotics potentiate neuromuscular blockade
Aminoglycosides (gentamicin, tobramycin) -  Ach release; lower sensitivity to ACh Tetracyclines – chelate Ca++ and  Ach release Clindamycin – block nicotinic receptors; depress muscle contractility Dose must be reduced when used together

Drug interactions Local anesthetics
Bupivacaine potentiates blockade by blocking neuromuscular transmission and muscle contractions Lidocaine and procaine prolong the duration of action of succinylcholine by inhibiting butyrylcholinesterase

Drug-disease considerations
Myasthenia gravis – resistance to succinylcholine but increased sensitivity to nondepolarizing agents; avoid long-acting agents Advanced age – prolonged duration due to decreased clearance by the liver and kidneys Hyperkalemia – potentiates depolarizing agents; antagonizes non-depolarizing agents Hypokalemia – potentiates non-depolarizing agents; antagonizes depolarizing agents

Drug-disease considerations
Renal disease – prolonged elimination of compounds that depend on glomerular filtration, tubular secretion and reabsorption for clearance Hepatic disease – prolongs the duration of blockade

Drug selection Considerations Onset of action Duration of action
Adverse effects (cardiovascular, respiratory) Renal/hepatic function Reversal Nondepolarizing agents can be reversed by cholinesterase inhibitors (neostigmine, physostigmine, pyridostigmine)

Which of the following NMBs is the DOC for intubation due to its short onset of action?
Pancuronium Vecuronium Succinylcholine Atracurium

Which of the following NMBs would you avoid in a patient with renal insufficiency (ClCr ~ 25 mL/min)? Atracurium Cisatracurium Pancuronium Rocuronium

Which of the following NMBs would you avoid in a patient with a history of malignant hyperthermia?
Atracurium Cisatracurium Pancuronium Rocuronium Succinylcholine

A 22-year-old patient underwent a surgical procedure
A 22-year-old patient underwent a surgical procedure. Anesthesia was provided by isoflurane, supplemented by intravenous midazolam (a benzodiazepine sedative) and pancuronium. Which of the following will reverse the effects of the pancuronium at the end of the procedure? What is its MOA? Aminoglycoside Bupivicaine Nitrous oxide Physostigmine

Lecture 7 Skeletal Muscle Relaxants
Explain the mechanism of action of muscle relaxants Describe indications and contraindications for this group of drugs Describe the most common adverse effects for these drugs

Introduction Musculoskeletal pain is common
Surveys indicate a yearly prevalence of low-back symptoms in 50% of working age adults 15% to 20% seek medical care 1 of 7 primary-care visits is prompted by musculoskeletal pain or dysfunction Musculoskeletal disorders are leading causes of disability and work absenteeism In 1990, an estimated $192 million were spent on medications for back pain in the United States Beebe et al. American Journal of Therapeutics 2005; 12:

Spasmolytics Antispasticity drugs Antispasmodic agents
 muscle cramping and tightness in neurological disorders, e.g., multiple sclerosis and cerebral palsy, spinal cord injury and disease Prevent use-related minor muscle spasms AKA centrally active muscle relaxants

Antispasticity Drugs Baclofen - Diazepam - Tizanidine – Dantrolene
Diazepam – Tizanidine- also anti-spasmotics

Spasticity Common neurological problem in patients with damage of central motor pathways Characterized by hyperexcitability of α-motorneurons in the spinal cord due to a loss of normal inhibitory function and an imbalance of excitatory and inhibitory neurotransmitters Antispasticity drugs alter the activity of neurotransmitters in the CNS and peripheral neuromuscular sites

Management of spasticity
Identify specific patient and caregiver objectives: Improve gait, activities of daily living, hygiene Provide pain relief, ease of care Decrease spasm frequency and pain CMAJ 2003;169(11):1173-9

Management of spasticity
Initiate comprehensive spasticity management program: Removal or treatment of noxious stimuli Physical/occupational therapies; proper positioning & regular stretching Oral drug therapy Injection of botulinum toxin type A Intrathecal baclofen Surgical intervention Start at the top and work your way down. CMAJ 2003;169(11):1173-9

Sites of antispasticity drug action

Drug Mechanism of action Baclofen
Binds to GABAB receptors on presynaptic terminals of spinal interneurons resulting in hyperpolarization of the membrane, decrease in Ca++ influx, decrease in excitatory neurotransmitters Diazepam Acts on GABAA receptors to enhance inhibition at pre- and postsynaptic sites in the spinal cord; it also acts in the brain Tizanidine Acts presynaptically at α-2 adrenergic receptors to inhibit spinal motor neurons Dantrolene Reduces Ca++-mediated excitation-contraction coupling through block of release channels on the sarcoplasmic reticulum of skeletal muscle

Baclofen: pharmacokinetics
Well absorbed; relative bioavailability: 70%–80% Time to peak concentration: 2–3 h Onset of action: hours to weeks (3 – 4 d) Widely distributed; crosses blood-brain barrier readily; protein binding: 30% Metabolism: minimal hepatic (15% of dose) Excretion: 70%–80% (parent compound in urine/feces) Elimination t 1/2: 2.5–4 h

Baclofen: adverse effects
Drowsiness initially; tolerance develops with chronic use Hypotension Elevated transaminases (ALT, AST, alkaline phosphatase) May cause positive stool guaiac Increase in serum glucose (hyperglycemia) Avoid abrupt withdrawal (hallucinations, seizures) Caution recommended in patients with seizures or renal impairment

Baclofen Continuous intrathecal baclofen is an option for patients unable to tolerate or unresponsive to oral therapy Pump/reservoir implanted between the muscle and skin of the abdomen A catheter carries baclofen from the pump to the spinal cord and nerves

Diazepam (valium): pharmacokinetics
Well-absorbed Time to peak concentration: 1-2 hours Onset of action: 15 – 30 minutes Widely distributed; crosses blood-brain barrier readily Metabolism: hepatic via CYP450 to n-desmethyl-diazepam (active metabolite) Multiple drug interactions! Excretion: urine as glucuronide conjugates Elimination t 1/2: > 48 hours Anything that causes sedation is a drug interaction for ALLL of the drugs in this presentation (ex. anti-histamines, sedatives, hypnotics, etc…) and metabolized via CYP450

Diazepam: adverse effects
Sedation, lightheadedness, ataxia, lethargy Impaired mental and psychomotor function Anterograde amnesia Physical dependence and withdrawal upon abrupt discontinuation Abuse potential (C IV) Pregnancy Category D: freely crosses the placenta and accumulates in fetal circulation

Tizanidine: pharmacokinetics
Bioavailability is 40% due to extensive hepatic first-pass metabolism (95%) Peak effect: 1–2 h Metabolism: hepatic via CYP 1A2; avoid with ciprofloxacin Excretion: urine (60%); feces (20%) Elimination t1/2: 2.5 h Caution in patients with renal insufficiency as clearance is reduced by 50%

Tizanidine: adverse effects
Tizanidine is an α-2 agonist similar to clonidine Dose-related hypotension, sedation and dry mouth Rare but severe hepatotoxicity; monitor transaminases (ALT, AST) Withdrawal and rebound hypertension with abrupt discontinuation; tapering is recommended

Dantrolene Drug of Choice (DOC) for malignant hyperthermia:
Pharmacokinetics Well absorbed Metabolism: hepatic CYP450 Excretion: urine/bile Elimination t 1/2: 15 h Adverse effects Hepatotoxicity with chronic use Drowsiness, dizziness, weakness, malaise, fatigue Drug of Choice (DOC) for malignant hyperthermia: high fever, tachycardia, hypertension, rigidity

Motor Nerve Blocker Botulinum toxin

Botulinum toxin type A Produced by anaerobic bacterium Clostridium botulinum MOA: Blocks the release of ACh from the motor nerves resulting in long-lasting muscle paralysis (~3 months) Used IM for: muscle disorders of the eye (blepharospasm, strabismus) elective cosmetic purposes spasticity, e.g., cerebral palsy Best for small areas of focal spasm Contraindicated in pregnancy & lactation

Antispasmodic drugs Chlorzoxazone – Cyclobenzaprine – Diazepam - Metaxalone – Methocarbamol – Orphenadrine - Tizanidine

Indications Painful musculoskeletal conditions including:
Low back pain Myofascial pain syndrome Fibromyalgia Tension headaches

Fast facts Among the top 200 drugs dispensed in 2006
However, NOT recommended as first line therapy Acetaminophen & NSAIDs are the DOC Use as adjuncts to physical therapy

? Pharmacology Unknown! Do not act on motor neurons or the muscle itself Act on the brain, maybe spinal reflexes CNS depressants  induce sedation Diazepam enhances the effects of GABA at receptors in the brain

Chlorzoxazone: pharmacokinetics
Readily absorbed Peak concentration: 1–2 h Metabolism: extensive hepatic phase II to glucuronides CYP 450 Substrate: 1A2, 2A6, 2D6, 2E1, 3/4 CYP 450 Inhibitor: 2E1, 3A4 Excretion: urine (conjugates); <1% excreted unchanged

Chlorzoxazone: adverse effects
Dizziness, drowsiness Red or orange urine Hepatotoxicity (rare); monitor LFTs Contraindicated in patients with hepatic dysfunction FDA Pregnancy category C

Cyclobenzaprine: pharmacokinetics
GOLD STANDARD DRUG= DRUG OF CHOICE Absorption: oral, complete Peak concentration: 3–8 h Protein binding: 93% Metabolism: extensive; conjugation to glucuronide CYP450 Substrate: 1A2, 2D6, 3A4 Elimination: renal (50%) inactive metabolites; unchanged drug in feces via bile Elimination t1/2: 1–3 d

Cyclobenzaprine: adverse effects
5-HT2 receptor antagonist, related structurally to cyclic antidepressants Tachycardia, hypotension, arrhythmias (rare), MI (rare) Drowsiness, lethargy, lightheadedness, dizziness Dry mouth, urinary retention,  intraocular pressure Seizures (rare) MOST evidence for efficacy Avoid with other serotonergic agents, recent MI, arrhythmias, glaucoma QT prolongation and possible torsade de pointes have been reported with fluoxetine, a CYP4502D6,3A4 inhibitor FDA Pregnancy Category B

Metaxalone: pharmacokinetics
Well absorbed; peak levels: 2-3 h Metabolism: hepatic CYP450 substrate 1A2, 2A6, 2D6, 2E1, 3/4A CYP450 inhibitor: 2E1, 3A4 Elimination: metabolites via kidney Elimination t1/2: 2.4h (fat meal) to 9.2 h (fasting)

Metaxalone: adverse effects
Drowsiness, dizziness, headache, nervousness Leukopenia, hemolytic anemia (rare)  hepatic transaminases Contraindications: significant renal/hepatic impairment; hypersensitivity FDA Pregnancy Category C

Methocarbamol: pharmacokinetics
Absorption: rapid and complete Peak serum concentration: h Distribution: widely throughout the body Metabolism: hepatic (first pass) Elimination t1/2: 1–2 h Elimination: renal 3d after 1 dose

Methocarbamol: adverse effects
Black, brown, or green urine Lightheadedness, dizziness, drowsiness FDA Pregnancy category C; fetal abnormalities have been reported

Orphenadrine: pharmacokinetics
Readily absorbed from GI tract, variable in overdose due to anticholinergic effects Peak effects: 2–4 h Widely distributed; protein binding: 20% Metabolism: hepatic Elimination: primarily renal (60%) metabolites, 8% parent compound Elimination t1/2: 14–16 h

Orphenadrine: adverse effects
Drowsiness, dry mouth, urinary retention, increased intraocular pressure Aplastic anemia (rare) Confusion Tachycardia Contraindications: glaucoma, myasthenia gravis Reduce dose in older patients FDA Pregnancy Category C

Carisoprodol Brand name: Soma
Metabolized to meprobamate, a C III controlled substance  physical & psychological dependence No better than any other SMRs DO NOT USE!!!

Safety Sedation – caution when driving or operating heavy machinery
Additive effects with alcohol or other sedative-hypnotics Caution in elderly

Evidence of effectiveness
Studies are not well-designed: Inadequate randomization No mention of allocation concealment Not using intention-to-treat methods Incomplete reporting of compliance

Evidence of effectiveness
A formal literature synthesis concluded that oral SMRs are effective in acute low-back pain and roughly equivalent to NSAIDs but found little evidence of effectiveness in chronic low-back pain it is not clear to what extent pain relief is affected by muscle relaxation versus the sedative effect of SMRs combinations of an SMR with an NSAID show increased efficacy over single agents

SORT: Key Recommendations for Practice
Clinical recommendation Evidence rating Skeletal muscle relaxants are not considered first-line therapy for musculoskeletal conditions. C Skeletal muscle relaxants may be used as adjunctive therapy for acute low back pain. B Antispasmodic agents should be used short-term (two weeks) for acute low back pain. There is no clear evidence that one skeletal muscle relaxant is superior to another for musculoskeletal spasms. Choice of skeletal muscle relaxant should be based on individual drug characteristics and patient situation. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see See et al. Am Fam Physician 2008; 78:

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