Many of the great achievements of the world were accomplished by tired and discouraged men who kept on working.

DLS-HSI medicine 2016

Subject: PHARMACOLOGY Topic: AUTONOMIC NERVOUS SYSTEM - 1 Lecturer: MARIA LUISA D. DELACRUZ, MD Date of Lecture: August 5, 2013; 10:00 am READ AT YOUR OWN RISK!

is a set of pathways to and from the central nervous system (CNS) that innervates and regulates smooth muscle, cardiac muscle, and glands is distinct from the somatic nervous system, which innervates skeletal muscle has two divisions: sympathetic and parasympathetic

Dual innervation, which occurs at most sites, means that a body organ receives neural innervation from both sympathetic and parasympathetic neurons on the ANS. Usually the effects are opposing except in the sex organs, in which the effects of SNS and PNS are complementary.

Characteristic Origin of Preganglionic Nerve

Sympathetic Nuclei of spinal cord segments T1T12; L1-L2 (thoracolumbar) Short

Length of preganglionic nerve axon Length of postganglionic nerve axon Preganglionic: Postganglionic fiber Response Location of ganglia

Parasympathetic Nuclei of cranial nerves III, VII, IX, and X; spinal cord segments S2-S4 (craniosacral) Long

Long

Short

1:20 Diffuse Paravertebral ganglia located on the either side of the vertebral column; prevertebral ganglia located anterior to the vertebral column Acetylcholine (Ach) Nicotinic Smooth and cardiac muscles; glands Norepinephrine (except sweat glands, which use Ach) 1, 2, 1, and 2 Prepares the body to cope with emergencies and intense physical activity Fight, flight, fright reaction

1:1 Discrete/Localized Near or in the wall of the target organ

SNS Action Pupillary dilation Eyes (mydriasis) Heart heart rate contractility AV node conduction Vascular smooth Constricts blood muscle vessels in skin; splanchnic Dilates blood vessels in skeletal muscle Gastro-intestinal motility tract Constricts sphincters Bronchioles Dilates bronchiolar smooth muscle Bladder Relaxes bladder wall Constricts sphincters sweating sweating lipolysis Ejaculation
NS;

Organ

PNS Action Pupillary constriction (miosis) heart rate contractility (Atria) AV node conduction -

motility Relaxes sphincters Constricts bronchiolar smooth muscle Contracts bladder wall Relaxes sphincters Erection
NS

Sweat glands Kidney Fat cells Male sex organs

Point and Shoot:

oint erection

hoot Ejaculation

Neurotransmitter in pre-ganglion fiber Receptor type in ganglion Effector organs

Acetylcholine (Ach) Nicotinic Smooth and cardiac muscles; glands Acetylcholine (Ach)

Neurotransmitter in effector organs (post-ganglionic) Receptor types in effector organs Functions

Muscarinic Conserves energy and replenishes energy stores; maintains homeostasis Rest and digest

Neurons do not act in isolation. They are connected via cell - cell interactions called SYNAPSES.

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1

| Page 1 of 8

DLS-HSI medicine 2016

There are two types of synapses: Chemical makes use of neurotransmitters Electrical utilizes ions b. HETERORECEPTOR respond to neurotransmitters, neuromodulator or neurohormones released from neurons or cells in the other system may be inhibitory or excitatory Examples: o Ach acting on M2 and M4 receptors inhibit release of NE from sympathetic neurons o NE acting on a2 receptors stimulate the release of Ach from parasympathetic neurons o NE acting on a2 receptors stimulate the release of serotonin from serotonergic neurons respond to neurotransmitter released by another neuron; may be inhibitory or excitatory

Structure of Chemical Synapse

2.

1921 Otto Loewi stimulate vagus nerve heart rate decreases Loewi hypothesized that stimulation of the vagus released a chemical first proof of chemical mediation of nerve action 1926 - Acetylcholine

POSTSYNAPTIC RECEPTORS located in the outer membrane of the postsynaptic neuron interaction with neurotransmitter result in localized increase in ionic permeability or conductance of the membrane Examples: o 1adrenoceptors o muscarinic receptors

Interaction with postsynaptic receptors

Production of post junctional potential

permeability to Na+ and Ca++ EPSP permeability to Cl IPSP permeability to K+ IPSP

EPSP results in depolarization while IPSP results in hyperpolarization

Before Loewi's experiments, it was unclear whether signalling across a synapse was bioelectrical or chemical. Loewi's famous experiment, published in 1921, largely answered this question. According to Loewi, the idea for his key experiment came to him in his sleep. He dissected out of frogs two beating hearts: one with the vagus nerve which controls heart rate attached, the other heart on its own. Both hearts were bathed in a saline solution (i.e. Ringer's solution). By electrically stimulating the vagus nerve, Loewi made the first heart beat slower. Then, Loewi took some of the liquid bathing the first heart and applied it to the second heart. The application of the liquid made the second heart also beat slower, proving that some soluble chemical released by the vagus nerve was controlling the heart rate. He called the unknown chemical Vagusstoff. It was later found that this chemical corresponded to Acetylcholine.
1. 2. Axonal conduction Junctional transmission 2.1 Release of neurotransmitter 2.2 Interaction with receptors 2.3 Production of response Termination of neurotransmitter action

a. b.

Reuptake (primarily) Enzymatic degradation Acetylcholinesterase (AChE) in PSNS Catechol-O-methyltransferase (COMT), monoamine oxidase (MAO) in SNS

3.

1.

PRESYNAPTIC RECEPTORS a. AUTORECEPTOR located in or close to axon terminals of a neuron through which the neurons own neurotransmitter can modify neurotransmitter synthesis and release Examples: o Acetylcholine (Ach) released from parasympathetic neurons interact with M 2 or M4 receptors to enhance Ach release o Norepinephrine (NE) released from sympathetic neurons interact with a2 receptors to inhibit release of NE inhibit or enhance release of neurotransmitter by the same neuron

Synthesis of Acetylcholine from Acetyl-CoA and Choline and its enzymatic degradation by acetylcholinesterase (AChE)

Enzymatic degradation of catecholamines by COMT and MAO

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1

| Page 2 of 8

DLS-HSI medicine 2016

MUSCARINIC RECEPTORS Subtype Location M1 CNS, gastric parietal cells, autonomic ganglia M2 Heart a. b. c. Inhibits Acetylcholine transport to the neuron terminal Hemicholinium Vesamicol Inhibits Acetylcholine release Botulinum toxin Stimulate Acetylcholine release Acetylcholine Latrotoxin o black widow spider Agonist / Antagonist at receptor site Interferes with destruction of neurotransmitter Acetylcholinesterase Inhibitor M3 M4 M5 smooth muscles, eye, secretory gland, endothelium CNS CNS G protein Gq PLC pathway Gi cAMP pathway Gq PLC pathway Gi cAMP pathway Gq PLC pathway

d. e.

Hemicholinium

NICOTINIC RECEPTORS Subtype Location Nm Neuromuscular junction Nn Autonomic ganglia, adrenal medulla Nn CNS (post synaptic / presynaptic

Signal Transduction permeability to Na+ permeability to Na+ permeability to Na+ permeability to Ca++

Vesamicol

Botulinum toxin

DIRECTLY-ACTING Natural and Naturally Synthetic Choline Occurring esters Cholinomimetic Alkaloids Acetylcholine Muscarine Methacholine Pilocarpine (Acetyl-b-methyl Arecoline choline) Nicotine Carbachol (Carbamyl choline) Bethanechol (Carbamyl methyl choline)

INDIRECTLY-ACTING Acetylcholinesterase Inhibitors

(do not directly act on the receptors)

M1 and M3

Activation of Gq-PLC pathway Hydrolysis of phosphoinositides to IP3 and DAG Mobilization of intracellular Ca++
M2 and M4

Activation of Gi cAMP pathway inhibit adenyl cyclase cAMP enhanced K+ conductance

hyperpolarization
a. Specific (True acetylcholinesterase) Neurons Synaptic clefts Neuromuscular junction Red blood cells Nonspecific (Pseudo-butyryl cholinesterase) Glial cells Plasma Liver Other organs

Subtype M1

Receptor Type

Postsynaptic

Location CNS

b.

Autonomic ganglia Gastric parietal cells Heart

M2

MUSCARINIC RECEPTORS
90% of cholinergic receptors in peripheral nervous system and brain slow, either excitatory or inhibitory G-protein coupled

NICOTINIC RECEPTORS
10% of cholinergic receptors in peripheral nervous system and brain fast, excitatory Ligand gated ion channels (sodium) activation increase permeability to Na+

Presynaptic Inhibitory (auto/hetero receptor)

M3

Postsynaptic

M4

Presynaptic Inhibitory
(auto/hetero receptor)

Smooth muscles Eye Secretory gland Endothelium CNS

Action memory, arousal, attention and analgesia Nicotinic cholinergic transmission in the ganglia Increase gastric acid secretion Decrease conduction velocity at sinoatrial and atrioventricular nodes decreased heart rate Contraction of smooth muscles miosis secretion of glands vasodilatation

M5

Postsynaptic

CNS

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1

| Page 3 of 8

DLS-HSI medicine 2016

3. 1. Central nervous system all muscarinic receptor subtypes present cognitive function, motor control, appetite regulation, nociception, memory, arousal, attention Cardiovascular system Direct effect o activation of M2 receptor in the SA node and atrial muscles Indirect effect o inhibition of NE release from sympathetic nerve terminals Remember, the muscarinic receptor present in the heart is M2, a presynaptic inhibitory type of receptor, which when acted upon by acetylcholine leads to hyperpolarization. Hyperpolarization of SA node: o (-)chronotropic effect decreased heart rate bradycardia Hyperpolarization of cardiac muscles: o (-) inotropic effect decreased force of contraction more effect on atrial muscles less dense cholinergic innervation of ventricles decrease rate of conduction in sinoatrial (SA) and atrioventricular (AV) nodes (-) dromotropic effect dilatation of blood vessels o Direct effect mediated by nitric oxidase synthase which synthesizes nitric oxide M3 is the muscarinic receptor found in endothelial cells Ocular M3 receptors in the constrictor pupillae and ciliary muscles

M3 in the constrictor pupillae

Contraction of constrictor pupillae muscle

2.

Miosis (pupillary constriction)

contraction of ciliary muscles accommodation loss of accommodation for far vision decrease IOP

4.

Gastrointestinal tract increase tone and amplitude of contraction increase secretory activity of glands in the stomach and intestines Genitourinary tract increase tone of detrusor muscle increase voiding pressure increase ureteral peristalsis relaxation of trigone and sphincter Respiratory increase secretion of tracheobronchial glands contraction of bronchial smooth muscles Other Glands increase secretions salivary sweat lacrimal pancreatic Sexual Function stimulate penile and clitoral arousal erection

5.

Activation of M3 by acetylcholine

Activation of nitric oxide synthase (NOS) NOS converts arginine to nitric oxide Nitric Oxide (NO) Nitric oxide (NO) will activate guanyl cyclase Guanyl cyclase converts GTP to cGMP cGMP Smooth muscle relaxation Vasodilation
8. 7. 6.

Acetylcholine Metacholine Carbachol Bethanechol Muscarine Pilocarpine

CVS ++ +++ + ++ +

GIT ++ ++ +++ +++ +++ +++

GUT ++ ++ +++ +++ +++ +++

RT ++ +++ -

Eye + + ++ ++ ++ ++

Glands ++ ++ ++ ++ +++ +++

Indirect Effect inhibition of the release of NE from adrenergic nerve endings mediated by Ach Net effect on BP: decreased BP hypotension o Vasodilation can lead to decreased total peripheral resistance (TPR) o The negative chronotropic effect can lead to decreased heart rate hence decrease in cardiac output (CO) o

Subtype Nm

Location Neuromuscular junction

Signal Transduction permeability to Na+

Effects Excitatory: Depolarization muscle contraction Excitatory: Depolarization of postganglionic neuron Secretion of catecholamine s Postsynaptic: Excitatory (depolarization of postsynaptic neuron) Presynaptic: control neurotransmitter release ( release)

Nn

Autonomic ganglia, adrenal medulla

permeability to Na+

Nn

CNS (post synaptic / presynaptic

permeability to Na+

permeability to Ca++

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1

| Page 4 of 8

DLS-HSI medicine 2016

Amanita muscaria - a poisonous mushroom produce mycetism contains the alkaloid muscarine and amatoxins from which was derived the name muscarinic receptor

1. 2. 3.

Autonomic ganglia PSNS and SNS adrenal medulla Epinephrine Neuromuscular junction depolarization contraction Central nervous system low dose excitatory high dose inhibitory

fatal dose of nicotine is approximately 40 mg, or 1 drop of the pure liquid equivalent to two regular cigarettes most of the nicotine in cigarettes is destroyed by burning or escapes via the "sidestream" smoke

Presence of methyl group less activity at nicotinic receptors Examples: o Methacholine o Bethanechol Carbamic acid esters are RESISTANT to hydrolysis by Acetylcholinesterase Examples: o Bethanechol o Carbachol

ACUTE NICOTINE TOXICITY 1. CNS stimulation Convulsions Coma respiratory arrest 2. Neuromuscular blockade skeletal muscle paralysis respiratory failure 3. Hypertension and cardiac arrhythmias CHRONIC NICOTINE TOXICITY 1. Addiction 2. Increase risk for coronary artery disease 3. Increase incidence of recurrences of peptic ulcer 4. Increase risk for malignancy

Susceptibility to Acetylcholinesterase Acetylcholine Methacholine Carbachol Betanechol Pilocarpine Muscarine +++ + -

Receptor Specificity Muscarinic +++ +++ ++ +++ ++ +++ Nicotinic ++ + +++ -

prevent hydrolysis of acetylcholine produce accumulation of acetylcholine at the cholinergic nerve terminals enhance cholinergic neurotransmission

Lipid solubility Oral absorption CNS penetration Excretion Examples

Quarternary Amine Less lipid soluble Poor Limited Kidneys (rapidly) Acetylcholine Betanechol Carbachol Metacholine Muscarine

Tertiary Amine More lipid soluble Good Good Kidneys; enhanced by acidification Arecholine Pilocarpine

Quarternary Amine Edrophonium Neostigmine Pyridostigmine Echothiphate

Tertiary Amine Tacrine/Donepezil Physostigmine Diisopfluorophosphate

Drug Acetylcholine
* has very short duration of action

Formulation 1% Ophthalmic solution Powder Diluted with 0.9% sodium chloride and administered via a nebulizer 0.01-3% Ophthalmic solution 5 mg, 10 mg, 25 mg or 50 mg Tablet

Methacholine

Therapeutic Use Induction of miosis during ophthalmologic surgery Diagnosis of bronchial airway hyperreactivity

Free AChE
Treatment of glaucoma; Induction of miosis during surgery Treatment of urinary retention (postoperative urinary retention, diabetic autonomic neuropathy, neurogenic bladder); postoperative abdominal distention, gastric atony, gastroparesis, adynamic ileus, and gastroesophageal reflux Treatment of glaucoma and as a miotic agent Xerostomia

Acetylated AChE

Carbachol

Bethanechol

Phosphorylated AChE

Carbamoylated AChE
Site of Action Central Peripheral Peripheral Peripheral Peripheral Peripheral Peripheral and Central

Pilocarpine

0.5-6% Ophthalmic solution or Ocular insert 5-10 mg Tablet

Tacrine / Donepezil Edrophonium Physostigmine Nesotigmine Pyridostigmine Echothiophate Diisopfluorophosphate (DFP)

Resultant Acetylcholinesterase Acetylated Acetylated Carbamoylated Carbamoylated Carbamoylated Phosphorylated Phosphorylated

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1

| Page 5 of 8

DLS-HSI medicine 2016

synthetic quaternary ammonium compound more polar do not pass thru the BBB 2-4 hrs duration of action dual action o reversible acetylcholinesterase inhibitor o direct activation of nicotinic receptor at the motor end plate beneficial in Myasthenia Gravis antidote for toxicity to Non-depolarizing Neuromuscular blocker

Edrophonium Tacrine Donepezil

Edrophonium binds to the ionic site of acetylcholinesterase. It is a short-acting inhibitor of acetylcholinesterase. EDROPHONIUM Quarternary amine Moderate Peripheral nervous system Rapid (10-20 mins) Diagnosis of myasthenia gravis (MG) TACRINE/DONEPEZIL Tertiary amine High Central Long Alzheimers Disease

Chemical structure Affinity for Acetylcholinesterase Site of action Duration of action Therapeutic use

synthetic quarternary ammonium compound used for long term treatment of Myasthenia gravis longer duration of action (4-6 hrs)

Carbamate Inhibitors o reversible Organophosphate Inhibitors o irreversible

inihibitory effect onacetylcholinesterase similar to organophosphates Pralidoxime use in carbamate toxicity can reduce the clinical severity mixed poisoning with organophosphorus compounds is common

These agents are esters of carbamic acid. The general formula is below.

Basic structure of Organophosphate Inhibitors react covalently with the enzyme at the esteratic site serve as true hemisubstrates Phosphorylated enzyme is extremely stable loss of physiologic function of the enzyme return of AchE activity depends on the synthesis of new enzyme stability of the phosphorylated enzyme is enhanced through aging which results from the loss of one alkly group

Carbamic acid

Basic structure of carbamyl inhibitors

Carbamylation and phosphorylation of AChE

react covalently with the enzyme at the esteratic site act as alternate substrate for Acetylcholinesterase hydrolyzed by Acetylcholinesterase much more slowly than Ach carbamylated enzyme is more stable; half-life is 15-30 minutes in vivo, the duration of inhibition by the carbamoylating agents is 3-4 hours enzyme function is NOT altered carbamoylated enzyme does not undergo aging spontaneous hydrolysis with consequent inactivation of the compound recovery of enzyme activity within several hours Examples: o Physostigmine o Neostigmine o Pyridostigmine o Ambenonium o Demecarium o Carbamate Insecticides: Propoxur Carbaryl Aldicarb

AChE, phosphorylated and inhibited by DFP

Examples: o Diisofluorophosphate (DFP) o Insecticides Malathion Parathion Diazinon Chlorpyrifos Malaoxon Paraoxon o Nerve gases Sarin Tabun Soman o Echothiophate iodide

Aged AChE

an alkaloid obtained from Physostigma venenosum tertiary amine 2-4 hours duration of action Topical formulation for treatment of glaucoma Systemic formulation for treatment of myasthenia

PHARMACOLOGICAL PROPERTIES OF ORGANOPHOSPHATES highly lipid soluble EXCEPT Echothiophate effectively absorbed from all routes endogenous Ach stimulates all cholinergic receptors (peripheral and CNS) low volatility and stability in aqueous solutions widely used as insecticides employed for home, garden and agricultural use converted to active metabolites by CYPs Malaoxon is derived from Malathion Paraoxon is derived from Parathion Parathion now phase out due to severe toxicity also use in suicide attempts or deliberate poisoning also used topically in the treatment of Pediculosis (lice infestations)

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1

| Page 6 of 8

DLS-HSI medicine 2016

high lipid solubility low molecular weight highly volatile absorbed from all routes: inhalation, transdermal and GIT absorption CNS penetration Antidote for Toxicity to: Anticholinergic drugs Tricyclic antidepressants Nondepolarizing (Competitive) neuromuscular blockers Pediculosis treatment of head and body lice Physostigmine, Neostigmine

Carbaryl Malathion

most potent synthetic toxins known extremely toxic used in warfare and terrorism attacks o March 20, 1995 Tokyo Sarin Attack

MYSTHENIC CRISIS vs CHOLINERGIC CRISIS

MYASTHENIC CRISIS extreme muscle weakness occurs due to inadequate medication (insufficient Ach at NMJ) There is improvement when given with Edrophonium (Tensilon) Treatment: Neostigmine, Pyridostigmine CHOLINERGIC CRISIS extreme muscle weakness caused by an overdose of a cholinesterase inhibitor (excessive cholinergic stimulation) Symptoms worsen when given with Edrophonium (Tensilon) Treatment: Atropine

only organophosphate used clinically ophthalmic use low lipid solubility non volatile

may be sequestered in lipids for long periods of time lipid soluble organophosphates are well absorbed from the skin volatile agents are transferred readily across the alveolar membrane COMPARISON OF ORGANOPHOSPHATES AND CARBAMATES

1.

2.

3.

Pesticides Propoxur Malathion Parathion Chemical warfare Sarin Soman Tabun Suicide (Deliberate poisoning)

1. 2. 3. 4.

Cholinergic syndrome Intermediate syndrome Organophosphate-induced delayed neuropathy (OPIDN) Organophosphorus-ester-induced chronic neurotoxicity (OPICN)

acute phase of acetylcholinesterase poisoning signs and symptoms result from activation of both muscarinic and nicotinic receptors vary depending on the balance bet muscarinic and nicotinic stimulation

CONDITIONS Glaucoma Xerostomia Gastrointestinal tract conditions Postoperative abdominal distension Gastric atony or gastroparesis adynamic ileus due to toxic states congenital megacolon Genitourinary tract conditions postoperative or postpartum urinary retention chronic hypotonic, myogenic, or neurogenic bladder partial sensory or motor paralysis of the bladder after spinal injury Myasthenia gravis neuromuscular disease characterized by severe weakness and fatigability of skeletal muscles loss of nicotinic receptors due to autoimmune mechanisms use of acetylcholinesterase inhibitors to increase Ach to stimulate limited receptors Alzheimers disease a neurodegenerative disease believed to be associated with decrease functioning of the cholinergic system in the brain

CHOLINERGIC AGONISTS Acute: Pilocarpine Chronic: Echothiophate Pilocapine Bethanechol Neostigmine

MANIFESTATIONS: 1. Clinical Signs due to Muscarinic Stimulation D diarrhea, diaphoresis U urination M miosis (pupillary constriction) B bradycardia, bronchospasm E emesis L lacrimation S salivation 2. Clinical Signs due to Nicotinic stimulation Mnemonic Monday Mydriasis Tuesday Tachycardia Wednesday Weakness and paralysis Thursday Hypertension Friday Fasciculations CNS effects confusion ataxia slurred speech generalized convulsions respiratory depression coma

Bethanechol Neostigmine 3.

For Diagnosis: Edrophonium (Tensilon Test) For Treatment: Neostigmine, Pyridostigmine

DIAGNOSIS: History of exposure Characteristic signs and symptoms Determination of RBC Cholinesterase activity

Tacrine Donezepil

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1

| Page 7 of 8

DLS-HSI medicine 2016

TREATMENT: 1. Prevention of secondary exposure 2. Supportive care 3. Antidote Atropine o Administer Atropine until full atropinization is achieved o Atropine effects are observed when there is increased heart rate and mydriasis Pralidoxime
4. The decrease in total peripheral resistance produced by cholinergic agonists is mediated by: a. Decrease in heart rate b. Release of cyclic GMP c. Blockade of alpha 1 receptors d. All of the above A decreased in blood pressure is observed after acetylcholine administration. This is attributed to: a. A decrease in total peripheral resistance b. A decrease in heart rate c. Decrease in cardiac output d. All of the above e. A and B only Hyperpolarization of the SA node results from activation of which of the cholinergic receptor? a. M3 b. M2 c. Nm d. Nn This choline ester has a long duration because it is resistant to hydrolysis by acetylcholinesterase? a. Methacholine b. Carbachol c. Bethanechol d. All of the above e. B and C only The cholinomimetic alkaloid that activate the muscarinic receptor but does not activate the nicotinic receptor: a. Pilocarpine b. Carbachol c. Neostigmine d. Acetylcholine Cholinergic agonist/s with less effects on the cardiovascular system will include: a. Pilocarpine b. Muscarine c. Carbachol d. All of the above e. A and C only This drug is used to regenerate phosphorylated acetylcholinesterase: a. Atropine b. Pralidoxime c. Both A and B d. Neither A nor B Which ion channel is linked to the nicotinic receptor? a. Na+ b. Clc. K+ d. Ca++ Which muscarinic receptor is linked to the cyclic AMP system? a. M1 b. M2 c. M3 d. All of the above e. A and C only The best recommended treatment for cholinergic crisis will include: a. pyridostigmine b. neostigmine c. atropine d. A and B only e. All of the above Drug/s that deplete the cholinergic nerve ending of its neurotransmitter include/s: a. Vesamicol b. Botulinum toxin c. Latrotoxin d. All of the above e. A and B only Fatality from organophosphate poisoning is usually due to: a. Cardiac arrhythmias b. Respiratory depression c. Anaphylactic shock d. All of the above e. A and B only

5.

ENZYME REACTIVATORS
Pralidoxime Obidoxime
6.

PRALIDOXIME 2-PAM (2-pyridine aldoxime methyl chloride) belongs to a class of chemicals, called oximes reverse the binding of cholinesterase inhibitors with acetylcholinesterase reverses the phosphorylation of cholinesterase improves neural synaptic transmission corrects muscle weakness and paralysis should be used within 24 hours of exposure early

7.

delayed onset of muscular weakness and paralysis occur between 24-96 hrs (1-4 days) after resolution of acute cholinergic syndrome and onset of OPIDN attributed to recirculation of cholinesterase inhibitors from adipose tissue major cause of morbidity and mortality Without hypoxic damage, spontaneously resolves in 1-2 weeks

8.

9.

rare delayed neurotoxic effect occurs 1-5 weeks after acute cholinergic syndrome symmetrical degeneration of spinal cord and peripheral nerves initial symptoms: sharp, crampy pain in the legs followed by stepping gait, quadriplegia damage to pyramidal tracts motor loss can be permanent

10.

11.

long term, persistent neuropsychiatric disorder Clinical findings consistent with brain damage due to hypoxia and seizures no specific treatment

12.

13.

JOHN PAUL II

14.

PRACTICE QUESTIONS
1. The activation of muscarinic receptors in bronchiolar smooth muscle is associated with a. activation of adenylyl cyclase b. decrease in CAMP formation mediated by G-proteins c. increase in IP3 and DAG d. inhibition of protein kinase C e. opening of Na+/K+ cation channels This organophosphate is a nerve gas commonly used in terrorist attack or for chemical warfare? a. carbaryl b. propoxur c. sarin d. malathion e. all of the above Activation of cholinergic receptors in the adrenal medulla will produce: a. Increased total peripheral resistance b. Increased cardiac output c. Neither A nor B d. Both A and B

15.

2.

3.

Itsmebob8
| Page 8 of 8

PHARMACOLOGY: AUTONOMIC NERVOUS SYSTEM 1