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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

know.” – Dr. Ramos

God bless 2018!