7

Introduction to ANS

7.1  INTRODUCTION TO ANS

Central NS

Nervous system (NS) is

categorized into
Peripheral NS

Somatic NS

Peripheral NS is classified
into
Autonomic NS (ANS)

ANS was named

by Langley

“Auto” = self, “Nomos” =

Introduction to ANS
governing (in Greek)

ANS is not under voluntary

control, i.e., is automatic
Sympathetic NS (SNS)

Controls viscera like heart,

smooth muscles
Parasympathetic NS (PSNS) Have opposing effects
Centers are present in
hypothalamus, medulla,
and spinal cord
SNS and PSNS both Are in state of equilibrium

Two important subdivisions

Innervate most organs

SNS is active i.e., Fight, flight, or

during Stress fright

PSNS is active i.e., Tissue-building

during Peace reactions

66
 Introduction to ANS  67

7.2  INNERVATIONS OF ANS

Autonomic afferents are carried in

e.g., 9th and 10th cranial nerves
visceral nerves (non-myelinated)

Myelinated preganglionic fibers →

synapse (ganglion) → postsynaptic
Autonomic efferents
fiber → receptor on organ
(neuroeffector junction)

Parasympathetic ganglia are

located near organ they supply

PSNS efferent are carried via Hence parasympathetic

CRANIOSACRAL outflow postganglionic fibers are small

Parasympathetic preganglionic
fibers are long Paravertebral

Innervations

Sympathetic ganglia are at Prevertebral

three places (T1-L3)

Sympathetic efferents carried via Sympathetic preganglionic Terminal

THORACOLUMBAR outflow fibers are short

Sympathetic postganglionic
fibers are ∴ long

Is a sympathetic ganglion

Different from other sympathetic

Adrenal medulla
ganglion

The main catecholamine

∴
is ADRENALINE
68  Pharmacology mind maps for medical students and allied health professionals

7.3 NEUROTRANSMITTERS

ANS neurotransmitters Acetylcholine, noradrenaline,

and dopamine

Adrenal medulla ADRENALINE, noradrenaline

Neurotransmitters
Other minor neurotransmitters
Nitric oxide (NO)
besides major ones

Co-transmission Modulate principle/major ATP (adenosine ATP, NO → inhibitory

neurotransmitters triphosphate) (gut)

e.g., VIP (vasoactive intestinal

peptide)

GABA (gamma amino

butyric acid)

CCK (cholecystokinin) CCK, VIP, GABA →

excitatory (gut)
 8
Cholinergic system and drugs

8.1  CHOLINERGIC SYSTEM

i. Ganglia: All preganglionic

ANS
(SNS and PSNS) fibers
Acetylcholine (ACh) is the
major neurotransmitter
of PSNS

ii. Postganglionic
parasympathetic
nerve terminals
Cholinergic nerves – synthesize,
Cholinergic system Introduction
store, and release ACh

iii. Adrenal medulla

Important ACh release sites

iv. Brain and spinal cord

v. Neuromuscular
junction (NMJ)

vi. Sympathetic
postganglionic nerve
terminals of sweat glands
(this is an unconventional site)

69
70  Pharmacology mind maps for medical students and allied health professionals

8.2  SYNTHESIS/TRANSMISSION/METABOLISM OF ACh

Acetyl CoA + choline →

acetylcholine (choline acetyl
tranferase [CAT])

Action potential at
presynaptic membrane

Release of ACh in synaptic cleft

Synthesis/transmission/ ACh binds and stimulates post-

metabolism of ACh synaptic cholinergic receptor

Depolarization of postsynaptic
membrane

Metabolism of ACh by
acetylcholinesterase
(AChE) in synaptic cleft

Repolarization of postsynaptic
membrane

8.3 CHOLINESTERASES

Acetylcholinesterase
ACh choline + acetic acid
True (acetylcholinesterase)
Cholinesterases present at neurons, ganglia, and
NMJ

2 types of AChE

Pseudo (butrylcholinesterase)
present in plasma and liver
 Cholinergic system and drugs  71

8.4  CHOLINERGIC RECEPTORS

Muscarinic

2 Types

Nicotinic

Muscarinic are of 5 subtypes M1, M2, M3, M4, and M5

Nicotinic are of 2 subtypes Nn and Nm

Muscarinic receptors are

G protein-coupled receptors

Nicotinic are ion

2α, 1β, 1γ, 1δ
channels and have 5 subunits

Cholinergic receptors
Autonomic ganglia, gastric
M1
glands, CNS

Heart, smooth muscles,

M2
nerves

Exocrine glands, smooth

M3
muscles, eye

M4,5 CNS

Nm NMJ

Autonomic ganglia, adrenal

Nn
medulla, CNS
72  Pharmacology mind maps for medical students and allied health professionals

8.5  CHOLINERGIC DRUGS

Act at same site as ACh

Mimic actions of ACh Acetylcholine,

Cholinergic i. Choline esters methacholine, carbachol,
drugs ∴ Called bethanechol
“cholinomimetics” or
Neostigmine,
“parasympathomimetics” ii. Cholinomimetic
Pilocarpine, muscarine physostigmine,
alkaloids pyridostigmine
Classification

Reversible Edrophonium
(short-acting)

Rivastigmine,
iii. Anticholinesterases CNS action, i.e., to Rx
galantamine,
Alzheimer disease
donepezil, tacrine

Echothiophate,
malathion,
Irreversible Organophosphates
toxic nerve gases
(sarin, tabun)
 Cholinergic system and drugs  73

8.6  ACTIONS OF ACh

Resembles alkaloid
muscarine present in
mushrooms

Due to stimulation of
muscarinic receptors
(M1–3) Resembles vagal
stimulation
a. Heart

Inhibits SA and AV node Hence ↓ HR and FOC Bradycardia

Due to release of
nitric oxide/EDRF
b. Blood vessels Dilatation (Endothelium
Derived Relaxing
Factor)
1. Muscarinic actions
↑ Tone and peristalsis,
GIT relaxes sphincters, hence
there is propulsion and
c. Smooth muscles ↑ Tone of all non-vascular
evacuation of GI contents
smooth muscles
Detrusor contracts, trigone
↑ Secretion of all glands, viz. Urinary bladder relaxes, hence it promotes
d. Secretory glands lacrimal, salivary, tracheo- evacuation of urine
bronchial, nasopharyngeal,
gastric, intestinal, and sweat

Constriction of sphincter
pupillae, leads to miosis

↑ Drainage of aqueous
e. Eye
humor, hence ↓ IOP

Ciliary muscle contraction

Resemble actions of
causes spasm of
alkaloid nicotine
accommodation
Actions of ACh 2. Nicotinic actions
Due to stimulation of
nicotinic receptor
i.e., Nn and Nm

Contraction of skeletal
muscles (Nm receptors)
a. NMJ
Higher doses result in
persistent contraction,
thus causing
spastic paralysis

Activates both
sympathetic and
parasympathetic ganglia
b. Autonomic ganglia
Activates adrenal
medulla

c. CNS Stimulates several sites

74  Pharmacology mind maps for medical students and allied health professionals

8.7  USES OF ACh AND CHOLINOMIMETICS

Rapidly metabolized in gut and

plasma (by pseudocholinesterase)
and at site of action
(by true cholinesterase)

Hence not used

Uses of ACh
therapeutically

Rarely used as 1% eye drops for

miosis during some eye operations

8.8  ADVERSE REACTIONS OF CHOLINOMIMETICS

Carbachol Glaucoma

Carbachol/Bethanechol
Uses of other cholinomimetics resistant to metabolism by Urinary bladder hypotonia
both cholinesterases, hence
long duration of action

Urinary retention
(mnemonic “SLUDGE”)
Bethanechol
Postoperative
S – Salivation paralytic ileus

Xerostomia (alternative to
L – Lacrimation pilocarpine)

Adverse reactions of
U – Urination
cholinomimetics

D – Diarrhea

G – GI/GU cramps

E – Emesis/Eye (miosis)
 Cholinergic system and drugs  75

8.9  CHOLINOMIMETIC ALKALOIDS

Source – Pilocarpus
microphyllus

Has prominent muscarinic

Miosis
actions

Spasm of accommodation
Actions on eye (important)
topically

↑ Sweating (diaphoresis) ↓ IOP

↑ Salivary secretion Browache due to spasm of

(sialogogue) accommodation and miosis

Cholinomimetic
Pilocarpine
alkaloids
Headache

Side effects

Corneal edema

Retinal detachment
(on long-term use)

As OCUSERT, a novel delivery

i. Glaucoma system which releases
pilocarpine for 7 days

ii. Alternatively with mydriatics To prevent/break adhesions

(pupillary dilators) between iris and lens
Uses
iii. Xerostomia (Sjögren's
syndrome)

iv. Dryness of mouth following

radiation of head and neck
76  Pharmacology mind maps for medical students and allied health professionals

8.10 GLAUCOMA

↑ In IOP (intraocular
pressure) beyond 21 mmHg

Aqueous humor is
produced by ciliary body

It drains via canal of

Glaucoma
Schlemm
Iris blocks canal of Schlemm
Acute congestive/angle
↑ In IOP leads to optic closure/narrow angle
nerve degeneration,
∴ causes blindness Should be treated urgently

2 Types of glaucoma
Slow onset

Chronic simple/open Long-term treatment is

angle/wide angle required

Surgical treatment is
usually preferred

8.11  DRUGS FOR GLAUCOMA

Timolol, betaxolol,
β blockers
levobunolol (first-line drugs)

Adrenaline, dipivefrine
Adrenergic agonists
(used with β blockers)
a. Drugs ↓ formation of
aqueous humor (all topical)

α2 adrenergic agonists Apraclonidine, brimonidine

Drugs for treatment of Carbonic anhydrase Dorzolamide (topical),

glaucoma inhibitors acetazolamide (oral)

Pilocarpine, carbachol,
Cholinergics
physostigmine, echothiophate
b. Drugs ↑ drainage of
aqueous humor
Latanoprost, bimatoprost
Prostaglandin analogs
(adjuvants)
 Cholinergic system and drugs  77

8.12  β BLOCKERS IN GLAUCOMA

e.g., Timolol

First-line drugs

↓ Aqueous production

β blockers in glaucoma Block β receptors in ciliary body

Hence there is no headache,

No miosis browache (unlike pilocarpine),
∴ preferred

Causes a smooth and sustained Can precipitate asthma, CCF,

↓ in IOP heart block

Systemic absorption via Hence are to be used carefully

nasolacrimal duct

Hence give pressure on

nasolacrimal duct
78  Pharmacology mind maps for medical students and allied health professionals

8.13 ADRENERGIC AGONISTS, MIOTICS, AND PROSTAGLANDIN

ANALOGS IN GLAUCOMA

e.g., Dipivefrine (a prodrug of

adrenaline), apraclonidine
(analog of clonidine)
Adrenergic agonists
in glaucoma
↓ IOP by reducing ciliary body
(α1-induced vasoconstriction)

e.g., Pilocarpine, physostigmine

Miotics

Thus opens up canal of Schlemm,

Constrict pupils
hence ↑ drainage

e.g., Latanoprost

Prodrug of PGF2α

Prostaglandin analogs
↑ Drainage by relaxing ciliary
muscle

Used as adjunct

8.14  CARBONIC ANHYDRASE INHIBITORS (CAIs)

e.g., Dorzolamide,
acetazolamide (oral)

Aqueous humor formation

requires HCO3– ions

Carbonic anhydrase HCO3– are produced by

H2CO3 → H+ + HCO3
inhibitors (CAIs) carbonic anhydrase

CAIs by inhibiting the

enzyme carbonic anhydrase
↓ HCO3, thus ↓ IOP

Oral acetazolamide leads

Hence topical dorzolamide
to hypokalemia, anorexia,
preferred
drowsiness
 Cholinergic system and drugs  79

8.15  ANTICHOLINESTERASES (ANTIChE)

Inhibits enzyme
cholinesterase (AChE)

Acetylcholine →
acetic acid + choline

Bind to cholinergic
AntiChE inhibits
receptors and
→ AChE
inactivates them

∴ ACh is not
Structural analogs
metabolized and
of ACh
accumulates at synapse
Anticholinesterases
(AntiChE)
∴ Their actions are
similar to ACh

AChE has 2 sites Anionic and esteratic

Physostigmine, neostigmine,
pyridostigmine, edrophonium,
Reversible Carbamates
donepezil, rivastigmine,
tacrine, galantamine

Insecticides Propoxur (Baygon),

Classification carbaryl, aldicarb
of AntiChE

Organophosphates

Irreversible
Echothiophate,
malathion, toxic nerve
gases (sarin, tabun)
80  Pharmacology mind maps for medical students and allied health professionals

8.16 PHYSOSTIGMINE

Natural alkaloid of
Source
Physostigma venenosum

Hence has a high lipid

solubility
Tertiary ammonium
compound
Thus it has a better oral,
CNS, tissue penetration

Glaucoma (with pilocarpine

nitrate)

Physostigmine Uses

Atropine poisoning

Browache

ADRs Retinal detachment

Availability – topical (0.1%–1%),

Cataract
IV injection

8.17 NEOSTIGMINE

Synthetically produced

Quarternary ammonium Hence has poor lipid

compound solubility
Neostigmine

As it has additional direct

Myasthenia gravis
action on NMJ

Postoperative paralytic
Uses
ileus

Urinary bladder atony

 Cholinergic system and drugs  81

8.18 EDROPHONIUM

Rapid and short-acting

To differentiate between
Edrophonium myasthenia crisis and
cholinergic crisis
Uses

IV for snakebite, curare

poisoning

8.19  RIVASTIGMINE, DONEPEZIL, GALANTAMINE, TACRINE

Rivastigmine, donepezil, Specifically used for

galantamine, tacrine Alzheimer's disease

8.20  USES OF REVERSIBLE ANTIChE

In glaucoma with
pilocarpine
1. As miotic
Alternating with mydratics
to prevent/break adhesions
between lens and iris ↑ Ch concentration
at NMJ
Chronic autoimmune
disorder Additionally has
direct stimulant
Characterized by nicotinic action on NMJ
receptor (NMJ) antibodies,
which ↓ NMJ receptor mass Hence muscle
Uses of reversible
AntiChE Leads to progressive skeletal power improves
muscle weakness and easy
fatigability Excessive muscle Due to infection, Can lead to
weakness surgery, stress MYASTHENIA CRISIS
Diagnosed by IV
edrophonium
Excessive muscle Due to ↑ dose of Can lead to
AntiChE; i.e.,
weakness neostigmine CHOLINERGIC CRISIS
Rx NEOSTIGMINE
15 mg QDS
CRISIS differentiated
2. Myasthenia by IV edrophonium
gravis 2 mg

IV edrophonium in Patient improves

myasthenia crisis

IV edrophonium in Patient worsens

cholinergic crisis

Rx of myasthenia
↑ Dose of AntiChE
crisis

Rx of cholinergic ↓ Dose of AntiChE,

crisis atropine
Glucocorticoids
to ↓ antibodies
Other Rx of myasthenia e.g., Azathioprine,
gravis cyclosporine
Immunosuppressants

↓ Antibodies

(Continued)
82  Pharmacology mind maps for medical students and allied health professionals

8.20  USES OF REVERSIBLE ANTIChE (Continued)

e.g., Antihistaminics, tricyclic

Toxicity of drugs with
antidepressants, and
anticholinergic actions
phenothiazine
3. Anticholinergic
poisoning/atropine
Because it has good tissue
poisoning
penetration (as it is a
tertiary amine)
Physostigmine preferred

Crosses BBB, hence it

neutralizes CNS toxicity also

As it has additional direct

4. Curare poisoning Neostigmine is preferred NMJ action besides
AntiChE action

5. Postoperative paralytic
ileus
Uses of reversible
AntiChE
6. Urinary bladder
atony/retention

Bite releases
∴
7. Cobra bite neurotoxin which paralyzes
skeletal muscles

To improve cholinergic
deficiency in CNS

8. Alzheimer’s disease

Specifically rivastigmine,
tacrine, donepezil

Irreversible AntiChE
9. Glaucoma echothiophate eye drops for
glaucoma
 Cholinergic system and drugs  83

8.21  IRREVERSIBLE ANTIChE (ORGANOPHOSPHORUS COMPOUNDS)

Powerful, irreversible inhibitors

of AntiChE

Binding is covalent to only

estaratic site and enzyme is
phosphorylated

Hence binding is stable and

irreversible

Reversible AntiChE (except

edrophonium) binds to both
Irreversible AntiChE anionic and estaratic site
(organophosphorus
compounds)
Edrophonium binds to only
anionic site, hence action is
quickly reversible and short-acting

All OP compounds (except

echothiophate) are highly lipid
soluble

Hence can be absorbed from all

routes, including intact skin

Thus, OP poisoning can also

occur by spraying of agricultural
pesticides/insecticides
84  Pharmacology mind maps for medical students and allied health professionals

8.22  ORGANOPHOSPHORUS POISONING

OP compounds are used as

agricultural insecticides/
pesticides

Hence poisoning
is frequent Similar to cholinergic
(muscarinic, nicotinic, CNS)
hyperactivity
Poisoning could be
accidental/suicidal/ i.e., SLUDGE (Salivation,
homicidal Lacrimation, Urination,
Diarrhea, GI/GU cramps,
Emesis/Eye – Miosis)
Signs/symptoms
Sweating, ↑ tracheobronchial
secretions, ↑ GI secretions,
Organophosphorus bronchospasm, hypotension,
poisoning convulsions, and coma

Respiratory paralysis can

cause death
Remove clothing

Poisoning via skin

Wash skin with soap

and water

Gastric lavage

Rx Maintain BP and
airway patency
IV 2 mg every 10 min until
pupil dilates/dryness
of mouth
ATROPINE

DRUG OF CHOICE

Poisoning via oral route

e.g., Pralidoxime

Pralidoxime combines with

cholinesterase–OP complex

Releases binding, frees

AChE enzyme

Administered within
Cholinesterase
minutes of poisoning
reactivators
(maximum 12–24 h)

Delay leads to “aging”

∴
of enzyme, cannot be freed

“Aging” is due to loss of one

chemical group from complex,
making complex stable

NOT USEFUL in carbamate

compound poisoning,
∴ they do not have a free site
(anionic site) for binding of oximes
 Cholinergic system and drugs  85

8.23  DIFFERENCES BETWEEN PHYSOSTIGMINE AND NEOSTIGMINE

Physostigmine Neostigmine

1. Natural (Physostigma venenosum) Synthetic

2. Tertiary amine Quarternary amine

3. Good oral absorption Poor oral absorption

4. Good tissue penetration Poor tissue penetration

5. Crosses BBB: CNS effects Does not cross BBB, no CNS effects

6. Main indication – glaucoma Myasthenia gravis

7. Used in atropine poisoning Used in curare poisoning

 9
Anticholinergics

9.1  INTRODUCTION AND CLASSIFICATION

Also called antimuscarinics,

parasympatholytics, or
cholinergic blocking drugs

Block effects of ACh on

Introduction
muscarinic receptors

Drugs that block nicotinic

receptors are ganglionic
blockers or neuromuscular
blockers Prototype, obtained from
Atropine Atropa belladonna, DOC
for OP poisoning
Anticholinergics Natural alkaloids

Scopolamine, for motion

Hyoscine
sickness

Homatropine (mydriatic)

Semisynthetic derivatives
Classification Ipratropium bromide, tiotropium
bromide (both for bronchial
asthma)

Mydriatics Tropicamide, cyclopentolate

Dicyclomine, propantheline,
Synthetic substitutes Antispasmodic–Antisecretory glycopyrrolate, telenzepine,
tolterodine

Benztropine, benzhexol,
Antiparkinsonian
trihexyphenidyl

86
 Anticholinergics 87

9.2 ACTIONS

↑ Heart rate,
causes tachycardia
1. CVS
Large doses lead
to hypotension

↓ All secretions, i.e., lacrimal,

salivary, gastric, tracheobronchial,
nasopharyngeal, except milk

↓ Sweating, results in fever;

ATROPINE FEVER
2. Secretions
↓ Salivary secretions lead to
dry mouth, dysphagia

↓ Lacrimal secretions lead to

dryness of eyes
↓ Tone and motility, hence
causes constipation
GIT

Relieves spasm

Relaxes ureters

Genitourinary Relaxes urinary bladder

Actions Hence they can cause urinary

retention, esp. in elderly
males with benign prostatic
3. Smooth hypertrophy (BPH)
muscles
Bronchodilation

Bronchi ↓ Tracheobronchial secretion

Hence provides symptomatic

Esp. ipratropium,
relief in chronic obstructive
tiotropium
pulmonary disease (COPD)

Relaxes smooth muscle

Biliary tract

Topical application blocks Hence relieves spasm

muscarinic receptors on sphincter
pupillae, which causes mydriasis,
4. Eye → ↑ IOP
Ciliary muscle are paralyzed;
paralysis of accommodation leads
to cycloplegia (blurring of vision)

High doses of atropine cause CNS

stimulation, leading to anxiety,
restlessness, hallucination, delirium
5. CNS
Scopolamine (hyoscine) causes
CNS depression, hence causes
sedation and drowsiness
88  Pharmacology mind maps for medical students and allied health professionals

9.3  ADVERSE EFFECTS

Dry mouth

Dysphagia

Constipation

Urinary retention

Adverse effects

Blurring of vision

Tachycardia, palpitations

Restlessness,
hallucinations, delirium

Toxicity is Rx with IV
physostigmine
 Anticholinergics 89

9.4 USES

Renal colic, along

with morphine

Biliary colic

Abdominal colic, along with

loperamide
1. Antispasmodic

Irritable bowel syndrome

Nocturnal enuresis

Post-urological surgeries

Iritis, iridocyclitis, keratitis,

Therapeutic following iridectomy
(to provide rest to eye)

Fundoscopy
Uses 2. Mydriatic and cycloplegic
Diagnostic

Testing errors of refraction

Alternating with miotics (e.g.,
pilocarpine, physostigmine) to
prevent/break adhesions
between lens and iris

Atropine 30 min before

anesthesia

↓ Salivary, tracheobronchial,
and gastric secretions

Prevents laryngospasm

3. Preanesthetic
Additional bronchodilatory
property

Prevents vasovagal attack

GLYCOPYRROLATE is
preferred

(Continued)
90  Pharmacology mind maps for medical students and allied health professionals

9.4  USES (Continued)

Drug of choice (DOC)

4. Organophosphorus (OP)
poisoning
2 mg IV every 10 min until
pupil dilates/dryness of
mouth

Transdermal (behind ear, on

5. Motion sickness mastoid) scopolamine 30 min
before journey

Ipratropium/tiotropium
bromide

Uses 6. Bronchial asthma and COPD Causes bronchodilation

Does not depress Hence there is no

mucociliary clearance inspissation of mucus in
(unlike atropine) respiratory passage

M1 blockers like
7. Peptic ulcer
pirenzepine/telenzepine

Centrally acting
anticholinergics

8. Antiparkinsonian/drug-
induced parkinsonism
e.g., Benztropine, benzhexol,
trihexyphenidyl