AUTONOMIC NERVOUS SYSTEM

Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

CHOLINERGIC AGONIST
- 1ST GROUP = cholinergic drugs, which acts on receptors that are activated by
acetylcholine
- 2ND GROUP = adrenergic drugs, which acts on receptors that are simulated by
norepinephrine or epinephrine
- cholinergic & adrenergic both act by either stimulating/blocking receptors of ANS

ACETYLCHOLINE SYNTHESIS

MUSCARINIC RECEPTORS NICOTINIC RECEPTORS

• present in certain
poisonous mushrooms
• found on ganglia of the
peripheral nervous system
• M1 = gastric parietal cells;
↑ HCl
• M2 = cardiac cells &
smooth muscles;
relaxation
• M3 = bladder, exocrine
glands & smooth muscle;
↑ secretion
• shows only a weak affinity or muscarine
• function as a ligand gated ion channel
• allows entry of sodium ions
• results in depolarization of the effector cell
(nicotine/acetylcholine) which initially
stimulates & then blocks receptor
• located in CNS, adrenal medulla, autonomic
ganglia & neuromuscular junction
• GANGLIONIC RECEPTOR = blocked by
hexamethonium
• NEUROMUSCULAR RECEPTOR = blocked
by tubocurarine
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

DIRECT ACTING CHOLINERGIC AGONIST

- AKA = Parasympathomimetic / lytic
- mimics the effects of acetylcholine by binding directly to cholinoreceptors
- have more longer durations of action than acetylcholine
- MUSCARINIC RECEPTOR/AGENTS = located primarily but not exclusively at the
neuroeffector junction of the parasympathetic nervous system
- shows little specificity in their actions which limits their clinical usefulness

2 GROUPS OF PARASYMPATHOMIMETIC
CHOLINE ESTERS NATURALLY OCCURING ALKALOIDS
Carbachol Pilocarpine – muscarinic receptors
Bethanechol – muscarinic receptors

1. ACETYLCHOLINE
- quaternary ammonium compound that cannot penetrate membranes
- a neurotransmitter of parasympathetic & somatic nerves
- has no therapeutic importance because of its multiplicity of actions & rapid
activation by the cholinesterases
- both muscarinic & nicotinic activity
ACTIONS
HEART ↓ heart rate & blood pressure
GASTRO ↑ salivary secretion
INTESTINAL Stimulates intestinal secretions & motility/peristalsis
Bronchiolar secretions enhanced; bronchoconstriction
GENITOURINARY Detrusor urine muscle ↑
TRACT Expulsion of urine
EYES Miosis; constriction of the pupil
Acetylcholine 1% solution is instilled to into the anterior chamber of
the eye to produce miosis during ophthalmic surgery

2. BETHANECHOL
- structurally related to acetylcholine which the acetate is replaced by carbamate
- hydrolyzed by acetylcholinesterase, due to the addition of carbonic acid
- lacks nicotinic actions
- have strong muscarinic activity
- MAJOR ACTION = bladder & gastrointestinal tract
- DURATION OF ACTION = 1 hour
ACTIONS
↑ intestinal motility, (+) peristalsis & expulsion of urine / diuresis
THERAPEUTIC APPLICATION
Stimulate atonic bladder in postpartum or postoperative
Nonobstructive urinary retention
Treat neurogenic atony & megacolon
ADVERSE EFFECTS
Cholinergic stimulations like sweating, salivation & flushing; ↓ BP & bronchospasm
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

3. CARBACHOL / CARBAMYLCHOLINE
- both muscarinic & nicotinic activity
- an ester of carbamic acid & poor substrate for acetylcholinesterase
- DURATION OF ACTION = 1 hour
ACTIONS
CARDIOVASCULAR Both have ganglion simulating activity which stimulate &
GASTROINTESTINAL depress these systems
Causes the release of epinephrine from adrenal medulla but its
nicotinic action
EYES Mimics the effects of acetylcholine
Causes miosis & spasm of accommodation
THERAPEUTIC USES
• Has high potency of receptor non-selectivity & relatively long duration of action
• rarely used therapeutically except in the eye as a miotic agent to treat glaucoma
• ↓ intraocular pressure
ADVERSE EFFECTS
• little or no side effect occurs due to lack of systemic penetration
• quaternary amine

4.PILOCARPINE
- tertiary amine
- hydrolyzed by acetylcholinesterase
- less potent but is in charged & will penetrate the CNS at therapeutic doses
- muscarinic activity
- used primarily in ophthalmology
- most potent stimulators of secretion
- promotes salivation
- XEROSTOMIA = excessive dry mouth; irradiation from the head & neck
ACTIONS
EYE Applied topically in the cornea
Rapid miosis
Contraction of the ciliary muscle
Vision is fixed making it impossible to focus
ATROPINE Alkaloid
Atropa belladonna
Adrenergic agent
Muscarinic blocker on the eye
THERAPEUTIC USES
• DOC for emergency in lowering of intraocular pressure for both narrow angle
(closed angle) & wide angle (open angle) glaucoma
• DURATION OF ACTION = 8 hours
• organophosphate echothiopate inhibits acetylcholinesterase
ADVERSE EFFECTS
• enters brain & causes CNS disturbance
• stimulates sweating & salivation
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

INDIRECT ACTING CHOLINERGIC AGONIST

- acetylcholinesterase cleaves acetylcholine to acetate & choline; terminates actions
- located both in the pre/post synoptically in the nerve terminal
- INHIBITORS = prolonging the lifetime of acetylcholine
- PARATHION = insecticides
- muscarinic & nicotinic activity

1. PHYSOSTIGMINE
- nitrogenous/alkaloids carbamic acid ester found in plants
- tertiary amine
- stable carbamylated
- reversibly inactivated
- potentiation of cholinergic activity throughout the body
THERAPEUTIC USES
• ↑ intestinal/peristalsis & bladder motility or urination/diuresis
• miosis & spasm of accommodation
• treat glaucoma
• antidote to overdosing like atropine, phenothiazine & tricyclic antidepressants

2. NEOSTIGMINE
- quaternary nitrogen
- more polar & does not enter the CNS
- stimulate contractility before it paralyzes
- DURATION OF ACTION = 30 minutes to 2 hours
- antidote for tubocurarine & other competitive neuromuscular blocking agents

3. PYRIDOSTIGMINE & AMBENOMIUM

- cholinesterase inhibitors
- used in the chronic management of myasthenia gravis
- DURATION OF ACTION = 3-6 hours & 4-8 hours
- duration of action is longer & adverse effects of agents is similar to neostigmine

4. DEMECARIUM
- cholinesterase inhibitor
- treats chronic open angle glaucoma
- used for diagnosis & treatment of esotropia
- quaternary amine
- related to neostigmine

5. EDROPHONIUM
- similar to neostigmine; atropine is the antidote
- DURATION OF ACTION = 10-20 minutes
- used in the diagnosis of myasthenia gravis
- leads to a rapid ↑ in intramuscular strength
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

6. TACRINE, DONEPRAZIL, RIVASTIGMINE & GALANTAMINE

- patients w/ Alzheimer’s disease have a deficiency of cholinergic neurons in the CNS
- possible remedies for the loss of cognitive function
- TACRINE = 1st to become available; replaced because of hepatoxicity
- DONEPRAZIL, RIVASTIGMINE & GALANTAMINE = delay the progress of disease

7. ECHOTIOPHATE
- paralysis of motor function which causes breathing difficulties & convulsions
- miosis & muscarinic
- used directly in the eye for chronic treatment of open angle glaucoma
- effects may last one week after single administration
- not a 1st line agent in the treatment of glaucoma
- potential risk for causing cataracts
PRALIDOXIME
• reactivate the inhibited acetylcholinesterase
• unable to penetrate into the CNS
• essential in the phosphate group
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

CHOLINERGIC ANTAGONIST
- lysis, destroy or anti
- cholinergic blockers / parasympatholytic
- anticholinergic
- does not trigger receptor mediated intracellular effects

ANTI MUSCARINIC AGENTS

- EX = atropine & scopolamine
- inhibition of muscarinic functions
- salivary & sweat glands
- no action at skeletal, neuromuscular junctions or autonomic ganglia
- antihistamine & antidepressant also has antihistaminic effects; 1+1=2 (addition)

1. ATROPINE
- tertiary amine belladonna alkaloid
- BELLADONNA = atropa
- high affinity for muscarinic receptor
- compete/prevent acetylcholine
- acts both centrally & peripherally
- 4 hours when administration is placed in the eye
ACTIONS
EYES Persistent mydriasis / dilation of pupil
CYCLOPLEGIA = Inability for near vision
GASTROINTESTINAL Antispasmodic – peristalsis (-)
Reduces the G.I tract activity
Gastric motility is reduced
Not effective in healing peptic ulcer; (+) HCl release
URINARY Reduced hypermotility
Common used in enuresis
involuntary voiding of urine among children
(-) diuresis / di maka ihi
CARDIOVASCULAR BRADYCARDIA = ↓ cardiac rate
TACHYCARDIA = ↑ heart rate
Sinoatrial node are block
1 mg of atropine required
TOXIC LEVELS = dilate the cutaneous vasculature
SECRETION Blocks the salivary glands / ↓ salivation
XEROSTOMIA = dry mouth
Sweat & lacrimal glands affected
DOSE & EFFECTS
0.5 mg Dry bone, cardiac slowing & inhibition of sweating
5 mg Tachycardia, xerostomia & mydriasis
>10 mg Hallucinations & delirium
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

MNEMONIC FOR ANTI MUSCARINIC TOXICITY: ALICE IN WONDERLAND

• HOT AS A HARE = ↑ body temperature
• DRY AS A BONE = dry mouth/skin & ↓ urination
• RED AS A BEET = flushed skin
• BLIND AS A BAT = cycloplegia & mydriasis
• MAD AS A HATTER = disorientation & hallucination

2. SCOPALAMINE
- tertiary amine belladonna alkaloid
- produces peripheral effects similar to those of atropine
- has greater action on CNS
- has longer duration of action in comparison to those of atropine
- CNS effect are observed at therapeutic doses
- EX = bonamine, hyoscine & buscopan
- AKA = rape drug & devils breath
ACTION
• most effective anti-motion sickness
• blocking short term memory
• produces sedation
• produces euphoria & is subject to abuse

3. IPATROPIUM
- quaternary derivative of atropine
- treat asthma who cant take adrenergic agonist
- bronchodilation
- beneficial for COPD / Chronic Obstructive Pulmonary Disease
- does not enter systemic circulation or CNS

4. TROPICAMIDE & CYCLOPENTOLATE

- ophthalmic solution
- mydriasis & cycloplegia
- DURATION OF ACTION = shorter
- MYDRIASIS = 6 hours
- CYCLOPENTOLATE = 4 hours
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

GANGLIONIC BLOCKERS
- act on nicotinic receptor of both parasympathetic & sympathetic
- blocks the ion channel & ANS at the nicotinic receptor
- non-selective
- not effective as neuromuscular antagonist

1. NICOTINE
- poison w/ undesirable actions
- w/o therapeutic benefits
- deteriols to health
- no function to health
- AVAILABLE = patches, lozenges, gums, etc.

2. MECAMYLAMINE
- competitive nicotinic blockage of ganglia
- DURATION OF ACTION = 10 hours after single administration
- TRIMETHAPAN = used to lower blood pressure in emergency

NEUROMUSCULAR BLOCKING DRUGS

- blocks cholinergic transmission between motor nerve endings & nicotinic receptors
- structural analogs of acetylcholine
- ANTAGONIST = nondepolarizing type
- AGONIST = depolarizing type
- used in surgery for producing complete muscle relaxation
- ↑ anesthetic doses

DEPOLARIZING
- use in intubation
- 2nd grade of muscle relaxant, central muscle relaxant to control spastic muscle tone
EXAMPLE
BENZODIAZEPINE / BENZODIAZEPAM Binds at GABA receptor
DANTROLENE Blocks calcium; (-) action potential &
hyperthermal by succinyl
BACLOFEN Neuropathic pain

NONDEPOLARIZING
- LIRARE = hunters used to paralyze in games on amazon
- introduced in 1940’s
- tubocurarine
AT LOW DOSE
Prevention of depolarization to inhibit muscle contraction
Competitive blocker
THERAPEUTIC
Adjuvant drugs in anesthesia during surgery to relax skeletal muscle & intubation
AUTONOMIC NERVOUS SYSTEM
Pharmacology 1
MIDTERM || (BS-Pharmacy, 2ND YR) | MAAM THESSALY NGO | 2ND SEMESTER 2023-2024

CHOLINESTERASE INHIBITOR
- neostigmine, physostigmine, pyridostigmine & edrophonium
- acetylcholine concentration

HALOGENATED HYDROCARBON ANESTHETIC

- halothane; enhances neuromuscular blockage

AMINOGLYCOSIDE ANTIBIOTICS
- gentamicin or tobramycin
- 1+1 = 3 (synergistic)
- enhancing the blockage

CALCIUM CHANNEL BLOCKER

- tubocurarine
- (-) depolarization