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Pharmacology
Autonomic Nervous System I
Agnes A. Carungcong, MD, FPBA, DPBPM
August 25, 2015
PERIPHERAL NERVOUS SYSTEM 1. AUTONOMIC NERVOUS SYSTEM (ANS)
• Visceral, vegetative, or involuntary nervous system
• Regulates autonomic function that occur without conscious control.
2. SOMATIC NERVOUS SYSTEM • Voluntary control of functions • Ex. Contraction of the skeletal muscles for
locomotion
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AUTONOMIC RECEPTORS GENERAL CLASSES • Cholinergic receptors
• Muscarinic 1-5 • Nicotinic muscle (Nm) • Nicotinic neuronal (Nn)
• Adrenergic receptors • α1, α2 • β1, β2 and β3
• Dopaminergic receptors • D1, D2, D3, D4, D5
NEUROHUMORAL TRANSMISSION
Transmission of impulses from postganglionic autonomic fibers to effector cells by means of
specific chemical neurotransmitters:
• Conduction – passage of impulse along an axon or muscle fiber.
• Transmission – passage of an impulse across a synaptic or neuroeffector junction
JUNCTIONAL TRANSMISSION
Arrival of the action potential at the axonal terminals initiating a series of events that trigger transmission of an excitatory or inhibitory impulse across the synapse or neuroeffector junction:
1. Storage & release of transmitter 2. Combination of transmitter with
postjunctional receptors & production of the postjunctional potential.
3. Initiation of postjunctional activity 4. Destruction or dissipation of transmitter 5. Non-electrogenic functions
PHARMACOLOGIC CONSIDERATIONS
CHOLINERGIC TRANSMISSION
ACETYLCHOLINE
mediates transmission of nerve impulses across autonomic ganglia in both sympathetic & parasympathetic nervous system
Acetyl CoA – derived from pyruvate via pyruvate dehydrogenase reaction or synthesized by acetate thiokinase
Choline – provided in the diet Choline acetyl transferase – final
step in ACh synthesis Acetylcholinesterase (AChE) –
removes /deactivates Ach @NMJ Re-uptake of Choline – rate limiting
step in ACh synthesis
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CHOLINERGIC RECEPTORS
Found in the central & peripheral nervous system & use acetylcholine (ACh) as neurotransmitter
AKA: “Acetylcholine receptors” (AChR)
2 main types: Nicotinic and Muscarinic
NICOTINIC RECEPTORS ① Nicotinic acetylcholine receptors
(nAChR)
Responsive to ACh & Nicotine “Ionotropic receptors” – or ligand
gated ion channels Rapid increase in cellular
permeability to Na+ and Ca2+, depolarization & excitation
Locations: skeletal NMJ, autonomic ganglia, adrenal medulla, CNS, non- neuronal tissues.
2 types of nAChR:
1. Muscle type (Nm) • Found in vertebrate skeletal
muscle • Mediate transmission at
neuromuscular junction (NMJ) 2. Neuronal type (Nn)
• Found in the peripheral nervous system, central nervous system, non-neuronal tissues
MUSCARINIC RECEPTORS
② Muscarinic acetylcholine receptors
(mAChR)
Responsive to ACh & Muscarine “Metabotropic receptors” – or G-
protein coupled receptors Slower, either excitatory or
inhibitory; not necessarily linked to changes in ion permeability
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A. DIRECT-ACTING CHOLINERGIC AGONISTS
Mimics the effects of ACh by binding directly to cholinoreceptors (muscarinic or nicotinic).
Longer duration of action than ACh.
2 groups: 1. Endogenous choline esters
• Acetycholine • Carbachol • Bethanechol
Note: Carbachol and Bethanechol are Synthetic esters of choline
2. Naturally occurring alkaloids • Nicotine • Pilocarpine
1. ENDOGENOUS CHOLINE ESTERS
ACETYLCHOLINE
METHACHOLINE
CARBACHOL
BETHANECOL
ACETYLCHOLINE
A quaternary ammonium compound The neurotransmitter of autonomic ganglia
and parasympathetic & somatic nerves. Rapidly inactivated by cholinesterases
(AChE) Has both muscarinic and nicotinic activity.
EFFECTS ON ORGAN SYSTEMS
HEART:
Mimics vagal stimulation
(-) chronotropy : ↓ cardiac rate
(-) dromotropy: ↓AV node conduction velocity
(-) inotropy: ↓force of contraction
↓ SA node firing: ↓ stroke volume Note: Normal vagal activity
regulates the heart by release of ACh at the SA node
↓ BP : vasodilation Activates M3 receptors in
endothelial cells of vascular smooth muscles
NO production from arginine: o Stimulates protein kinase G
production ☞
hyperpolarization / phosphodiesterase-3-
inhibition ☞ smooth muscle
relaxation GI:
↑salivary secretion / intestinal secretion
↑ intestinal motility Lungs:
↑bronchiolar secretions Genitourinary tract:
↑tone of detrusor muscle – allowing urination
Eye:
↑ ciliary muscle contraction for near vision
Miosis : Constriction of the pupillae sphincter muscle
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BETHANECHOL
An unsubstituted carbamoyl ester,
structurally related to ACh. Not hydrolyzed by AChE No nicotinic activity; Strong muscarinic
activity Major actions are on the smooth muscles of
bladder & GI tract.
ACTIVITY ON ORGAN SYSTEMS
GI
↑motility & tone Genitourinary tract
Stimulates detrusor muscle in the bladder
Relaxes trigone & sphincter muscles = URINATION
THERAPEUTIC USES
Atonic bladder:
Post-partum Post-operative Neurogenic urinary retention
Megacolon
ADVERSE EFFECTS
Effects expected of cholinergic stimulation: Sweating Salivation Flushing ↓BP Nausea Abdominal pain Diarrhea Bronchospasm
CARBACHOL
Has both muscarinic & nicotinic actions An ester of carbamic acid and a poor
substrate for AChE – longer lasting than acetylcholine
Pharmacokinetics:
Onset: 2-5 mins
Duration: 4-8 hrs; 24 hrs by intraocular administration
EFFECTS ON ORGAN SYSTEMS
Cardiovascular & GI systems:
(+) ganglion stimulating activity o Stimulate first then depress
(+) release of Epinephrine from adrenal medulla by its nicotinic action
Eye
Mimics Ach
Miosis & spasm of accommodation: ciliary muscle of the eye remains in constant contraction
THERAPEUTIC USES
Glaucoma
Pupillary contraction ↓intraocular pressure
Rarely used therapeutically: High potency Receptor non-selectivity Relative long duration of action
2. CHOLINOMIMETIC ALKALOIDS
(NATURAL & SYNTHETIC)
PILOCARPINE
MUSCARINE
ARECHOLINE
PILOCARPINE
A tertiary amine and is stable to hydrolysis by AChe
Exhibits muscarinic activity Used primarily in ophthalmology
EFFECTS ON ORGAN SYSTEMS
Eye
Rapid miosis and contraction of the ciliary muscle
(+) spasm of accomondation o Difficult to focus – vision
becomes fixed at some particular distance
Glands
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Potent stimulators of secretions: sweat, tear, saliva
THERAPEUTIC USE
Ophthalmologic: Glaucoma
o DOC for emergency lowering of intraocular pressure of both open-angle and angle-closure glaucoma. Extremely effective in opening
the trabecular meshwork around the Schlemm canal
↑drainage of aqueous humor. Reversal of mydriasis due to atropine
ADVERSE EFFECTS
Blurred vision Night blindness Brow-ache
“Pilocarpine poisoning”
• Exaggerated parasympathetic effects: Profuse sweating (diaphoresis) Salivation
• Antidote: ATROPINE
B. INDIRECTLY ACTING CHOLINERGIC AGONISTS
Acetylcholinesterase (AChE) An enzyme that cleaves ACh to acetate
& choline, terminating the actions of acetylcholine (Ach)
Anticholinesterase or Cholinesterase inhibitors (anti-AChE)
Provoke response to both muscarinic & nicotinic receptors of ANS.
Provide cholinergic action by preventing the degradation of Ach.
Accumulation of Ach in the synaptic space. 2 groups:
Short-acting
Intermediate-acting agents
Butyrylcholinesterase (BChE, pseudocholinesterase) Widely present, including a presence in
soluble form in plasma Broader substrate specificity than AChE;
hydrolyses butyrylcholine more efficiently than acetylcholine
together with AChE, keeps acetylcholine concentration in plasma nearly undetectable.
REVERSIBLE CHOLINESTERASE
INHIBITORS
EDROPHONIUM
Prototype short-acting AChE inhibitor Quaternary amine; actions are limited to
periphery. MOA:
• Reversibly binds to the active center of AChE, preventing hydrolysis of ACh.
Pharmacokinetics: • Rapidly absorbed • Short duration of action: 10-20 mins • Rapid renal elimination
DIAGNOSTIC & THERAPEUTIC USES
Diagnosis of Myasthenia gravis
• An autoimmune disease caused by antibodies causing degradation of nicotinic receptor at the NMJ, resulting in fewer receptors available for interaction with Ach.
Edrophonium “Tensilon” test: • IV Edrophonium 2 mg administered as
test dose • If no response in 2 minutes, up to
additional 8 mg is injected
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• (+) test: rapid ↑ in muscle strength in 30-45 seconds
• Differentiates cause of muscle weakness: Cholinergic vs. myasthenic crisis.
DIAGNOSTIC & THERAPEUTIC USES
Differentiates cholinergic and myasthenic
crises Reversal of non-depolarizing
neuromuscular blockers
PHYSOSTIGMINE
A tertiary amine, nitrogenous carbamic acid
ester from plants Reversibly inhibits AChE, resulting in
potentiation of cholinergic activity. Stimulates muscarinic, nicotinic receptors in
ANS; and nicotinic receptors in NMJ Intermediate acting (Duration of action: 30 mins-2 hours)
THERAPEUTIC USES
Intestinal atony Bladder atony Treatment of overdoses with anticholinergic
drugs: ATROPINE, phenothiazines, antihistamines, TCA
“Central anti-cholinergic syndrome” reversal
ADVERSE EFFECTS
Convulsions (high doses) Bradycardia ↓cardiac output Paralysis of skeletal muscles (high dose)–
due to inhibition of AChE causing accumulation of Ach “Cholinergic Crisis”
Overstimulation of NMJ due to excess ACh (or anti-AChE)
Muscles stop responding to bombardment of ACh leading to flaccid paralysis and respiratory failure +/- miosis, ↑sweating, salivation, bronchial secretions.
“Tensilon Test” to differentiate muscle weakness due to cholinergic vs. myasthenic crisis
NEOSTIGMINE
A synthetic carbamic acid ester that
reversibly inhibits acetylcholinesterase. Targets NMJ and can be used orally for
treatment of MG and reversal of muscle relaxants such as gallamine and tubocurarine.
Does not cross BBB (unlike Physostigmine)
THERAPEUTIC USES
Paralytic ileus o Dose: 0.5mg given as needed o Peristaltic activity commences:
10-30 mins after SQ neostigmine methyl sulfate
2-4 hrs after oral neostigmine bromide
Urinary bladder atony Symptomatic treatment of MG Reversal of neuromuscular blockade
DRUG WARNINGS
Precautions/ Contraindications:
Cardiac dysrhythmias Bronchial asthma Mechanical obstruction of intestine or
urinary bladder Presence of peritonitis Bowel viability is doubtful
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PYRIDOSTIGMINE
MOA similar to neostigmine Therapeutic use:
o Chronic management of Myasthenia gravis (neostigmine, pyridostigmine, ambenonium)
o Duration of effect: Neostigmine: 2-4 hrs Pyridostigmine: 3-6 hrs Ambenonium: 3-8 hrs
Adverse effects: common to all anti-AChE
TACRINE
Tetrahydroaminoacridine approved for use in mild to moderate Alzheimer's disease
o Alzheimer's disease: deficiency of intact cholinergic neurons in the subcortical areas of the brain: nucleus basalis of Meynert.
o CNS degenerative disease: Progressive dementia
Pharmacokinetics: o Low bioavailability o Short half life (needed to be
administered several times /day Adverse effects:
o Hepatotoxicity (↑alanine aminotransferase)*
o Typical peripheral side effects of AChE inhibitors: diarrhea, N/V, urinary incontinence
DONEZEPIL
Centrally acting, selective & reversible cholinesterase inhibitor in the CNS.
↑concentration of ACh at central cholinergic synapses.
Pharmacologic Use: o Alzheimer’s disease
Pharmacokinetics: o Well absorbed after oral admin. o Crosses BBB
o T ½ : long (70 hours) , administered once a day
Adverse effects: o Bradycardia, diarrhea, nausea and
vomiting -- mild o Not associated with hepatotoxicity
(unlike Tacrine)
IRREVERSIBLE CHOLINESTERASE INHIBITORS
(ORGANOPHOSPHATES)
ORGANOPHOSPHATE ANTI-
CHOLINESTERASES
High lipid solubility/ high vapor pressure = high risk of toxicity
Generally dispersed as aerosols or as dusts Pharmacokinetics: Absorbed rapidly through the:
o Skin and mucous membranes following contact with moisture
o Lungs after inhalation o GI tract after ingestion
Metabolism: plasma and liver esterases Excretion: Urine as hydrolysis products
DIISOPROPYL FLUOROPHOSPHATE
A potent irreversible inactivator of cholinesterase and other esterase by alkylphosphorylation.
Highly toxic, very volatile, and resembles hydrocyanic acid and parathion in toxicity.
Signs & Symptoms of toxicity: o Mild: headache, anorexia, weakness,
dizziness, blurred vision, miosis o Moderate: vomiting,
abdominal/muscle cramps, sweating, dyspnea, substernal tightness, tremors
o Severe: cyanosis, pulmonary edema, areflexia, loss of sphincter control, coma, seizures, resp. failure
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ECHOTHIOPATE IODIDE
An organophosphate that covalently binds to the active site of AChE and permanently inactivates it
“aging” – loss of alkyl group, makes it impossible for chemical reactivators, such as pralidoxine to break the bond between the drug and the enzyme.
ACTIONS
Generalized cholinergic stimulation Paralysis of motor function (difficulty of
breathing) Convulsions Intense miosis
ATROPINE – (in high dosages) reverse
many peripheral and some of the central muscarinic effects of Echothiopate.
THERAPEUTIC USE
Open-angle glaucoma
(Topical ophthalmic solution) (miosis) facilitates outflow of aqueous
humor. Rarely used due to its side effect profile:
Cataracts
MALATHION
Uses: o Insecticide: used for aerial spraying
of citrus-orchard mediterranean fruit flies and mosquitoes.
o Topical use in the treatment of pediculosis (lice) infestation.
(+) resistance to mammalian species o This insecticide can be detoxified by
hydrolysis of the carboxyl ester linkage by plasma carboxylesterases of mammals.
Deliberate poisoning / suicide attempts:
o Lethal dose: 1 g/kg; skin exposure (<10% systemic absorption)
PARATHION
A phosphorothioate Most widely used insecticide
o Low volatility and stability in aqueous solution
“paraoxon” – active metabolite Exposure routes: inhalation, skin
absorption, ingestion, eye contact Target Organs: Eyes, skin, respiratory
system, CNS, CVS, blood cholinesterase
NERVE GASES: TABUN, SARIN, SOMAN
Most potent & toxic synthetic warfare
agents known. Volatile agents/ soluble in fat & water/
denser than air: o Dermal contact o Eyes o Respiratory : Inhalation of vapor
ACUTE INTOXICATION: DIAGNOSIS
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History of exposure Characteristic signs & symptoms Determination of cholinesterase activity in
erythrocytes & plasma – will confirm the diagnosis
*** Respiratory Failure - common cause of death.
o Laryngospasm, bronchoconstriction, ↑tracheobronchial / salivary secretion, compromised voluntary control of diaphragm & intercostal muscles, central respiratory depression.
o Time of death: <5 minutes to 24 hours
ACUTE INTOXICATION: GENERAL SUPPORTIVE MEASURES
Termination of exposure:
o removal of contaminated clothing, copious washing of contaminated skin or mucous membrane, gastric lavage
Maintenance of patent airway Artificial respiration, if required Alleviation of convulsions : Diazepam 5-10
mg IV Treatment of shock
ACUTE INTOXICATION: SPECIFIC TREATMENT
Atropine 2-4 mg IV/IM initially, then 2 mg
q 5-10 mins until muscarinic symptoms disappear.
o Antagonizes the actions at muscarinic receptor sites: ↑tracheobronchial & salivary secretions, bronchoconstriction, bradycardia
o No effect against peripheral neuromuscular compromise
ACUTE INTOXICATION: TREATMENT
Pralidoxine 1-2 g IV infusion >5mins,
repeat as necessary every 20-60 minutes o Reactivates inhibited AChE o Cannot overcome toxicity of
reversible AChE inhibitors (ex. physostigmine)
o Antagonizes muscarinic & nicotinic actions at the NMJ of skeletal muscles , but not CNS effects: fatigability, generalized weakness, involuntary twitching, fasciculations, paralysis of respiratory muscles
NICOTINIC RECEPTOR AGONIST
NICOTINE
2nd to caffeine as most used CNS stimulant 2nd to alcohol as most abused drug MOA:
o Initially stimulates the ganglia by an acetylcholine-like action and then blocks them by causing a persistent depolarization.
Low dose: ganglionic stimulation by depolarization
High dose: ganglionic blockade
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ACTIONS
CNS
o Highly lipid soluble; readily crosses BBB
o Euphoria, arousal, relaxation, improved attention, learning, problem solving, reaction time, appetite suppressant
o Nicotine toxicity: central respiratory paralysis, severe hypotension sec. to medullary paralysis
Peripheral effects o Stim. of sympathetic ganglia: ↑BP
/HR; exacerbation of peripheral vascular disease; ↓coronary blood flow (nicotine-induced vasoconstriction)
o Stim. of parasympathetic ganglia: ↑bowel motility;
o At high doses: nicotine-induced block of parasympathetic ganglia: ↓BP, ↓GI motility/bladder musculature
PHARMACOKINETICS
NOT CURRENTLY USED
THERAPEUTICALLY (except for smoking
cessation therapy – NICOTINE PATCH/GUM)
Absorption: readily occurs via oral mucosa, lungs, GI, skin (90%)
In Tobacco: 1-2 mg /cigarette Lethal dose: 60 mg Metabolism & Clearance: lung, liver,
urinary
ADVERSE EFFECTS
Irritability Tremors Intestinal cramps Diarrhea ↑BP / HR ↑ rate of metabolism for a number of drugs. Withdrawal syndrome: restlessness,
difficulty concentrating, headaches, insomnia, GI upset
DIMETHYPHENYLPIPERAZINIUM
(DMPP)
A potent synthetic nicotinic acetylcholine receptor agonist/stimulant which is selective for stimulation of autonomic ganglion cells and end-plates of skeletal muscle.
Hypertensive agent o Pressor effect depends upon release
of epinephrine / NE from adrenal glands and liver and stimulation of sympathetic ganglia
o (+) vasoconstriction and cardioaccelaration
TOXICITY CHOLINERGIC AGONISTS
I. ACUTE TOXICITY
1. MUSCARINIC EXCESS
• Miosis • Nausea, vomiting • Salivation, sweating • Cutaneous vasodilation • Bronchospasm
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2. NICOTINIC EXCESS • CNS stimulation – convulsion, coma • Neuromuscular blockade – respiratory
failure • CVS – hypertension, arrhythmias
II. CHRONIC TOXICITY
Peripheral nerve demyelination
• Progressive muscle weakness • Sensory loss
MANAGEMENT
1. General Measures: • Maintain vital function • Decontamination
2. Specific Measures
• Atropine 2-4 mg IV/IM initially, then 2 mg q 5-10 mins until muscarinic symptoms disappear.
o antagonizes the actions at muscarinic receptor sites: ↑tracheobronchial & salivary secretions, bronchoconstriction, bradycardia
o No effect against peripheral neuromuscular compromise
Specific Measure: Enzyme Reactivators
• Pralidoxine 1-2 g IV infusion >5mins,
repeat as necessary every 20-60 minutes o Reactivates inhibited AChE o Cannot overcome toxicity of
reversible AChE inhibitors (ex. physostigmine)
o Antagonizes muscarinic & nicotinic actions at the NMJ of skeletal muscles , but not CNS effects: fatigability, generalized weakness, involuntary twitching, fasciculations, paralysis of respiratory muscles
DRUG INTERACTIONS
Acetylcholinesterase + Aminoglycosides
o Potentiates inhibition of acetylcholine release ↑blocking effect on NMJ
Neostigmine + Non-depolarizing neuromuscular blocker
o Reversal of neuromuscular blockade by non-depolarizing muscle relaxant
Neostigmine + Succinylcholine o Succinylcholine is a depolarizing
neuromuscular blocker that first activates AChR causing initial fasciculations, then relaxation occurs.
o Neostigmine will contribute to the initial depolarization and will block pseudocholinesterase, which is needed to break down ACh.
-------------------------END OF TRANX--------------------- Pure powerpoint trans, no recordings were added. Doc Carungcong’s references are Lippincott 6th ed. and Goodman and Gilman’s 12 ed. Read at your own risk!
“That’s why Medicine is divided into so many specialties, to remind you how much you don’t
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