Autonomic 

Pharmacology 

CHOLINERGIC PHARMACOLOGY
Synthesis of Acetylcholine (ACh)
• Choline is transported by a membrane carrier from the extracellular fluid into
the cholinergic neuron where it is acetylated in the cytoplasm by acetyl CoA
forming ACh. The reaction is catalysed by choline acetyl transferase.

Storage & Release of ACh (inhibited by botulinum toxin i.e. antispasmotic)

• ACh is stored in small membrane-bound vesicles, which are concentrated in
the terminals of cholinergic neurons. Arrival of an action potential triggers
Ca2+influx, which stimulates release of ACh by partial exocytosis.
• Action of ACh is terminated by rapid hydrolysis by acetylcholine esterase.

Control of ACh release by presynaptic receptors

• MMCMP 407
2 inhibitory (dominant).

• Nn facilitatory (ensures continuous supply of Ach in motor nerves).

Pharmacologic manipulation of the cholinergic system
Ca 2
+

Na+
Muscarinic
ACH Receptor
Choline
Acetyltransferase
Acetylcholinesterase
Acetyl CoA
+ Acetylcholine
Action Potential Choline
α
α β

Na+ H+
ACH Nicotinic
Choline Acetate
Receptor
Choline

Presynaptic neuron
Postsynaptic target

Synthesis, Storage, Release & Fate of ACh

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 Autonomic Pharmacology 

Cationic head
4ry N+ of choline
Acetyl gp
N+
I. Binding

II. Cleavage

Acetylated Enz + Choline

III. Hydrolysis

Acetate Free Enzyme

Degradation of Acetylcholine
• ACh is degraded by choline esterase enzyme through 3 steps:
1. Binding: The acetyl (ester) group of ACh binds to the esteratic site of the
enzyme by a covalent bond & the N+ (cationic) head binds to the anionic
site by a weaker ionic bond.
2. Cleavage: choline is cleaved leaving the acetylated enzyme.
3. Hydrolysis: hydration of acetylated enzyme releases acetate & the free
enzyme.
Types of Choline Esterases
• True (AChE): Present at terminals of cholinergic fibers & RBCs. Specific
for ACh , essential for life with slow regeneration in 120 days.
• Pseudo ChE: Present in plasma. Nonspecific → hydrolyzes other esters as
succinylcholine. Not essential for life, rapidly regenerated by the liver.

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 Autonomic Pharmacology 

CHOLINERGIC RECEPTORS
• ACh mediates its effects by activating muscarinic & nicotinic cholinergic
receptors present centrally & peripherally:

I. Muscarinic receptors (blocked by atropine)

1. M1 receptors (excitatory) : coupled to Gq → ⊕ PLC → ↑ DAG & IP3 →
• CNS→ excitatory
Involved in arousal, learning & short-term memory (↓ Ach → Alzheimer
dementia).
• Gastric enterochromaffin like cells → histamine release → ↑HCL

2. M2 receptors (inhibitory): coupled to Gi → \ adenylyl cyclase →

• Heart → inhibitory
• Presynaptic neurons → inhibit ACh release.

3. M3 receptors (excitatory): coupled to Gq → ⊕ PLC → ↑ DAG & IP3. →

• Smooth muscles→ stimulate wall (bronchi, GIT,urinary) & relaxes sphincters.
• Eye → miosis (⊕ constrictor pupillae) - accommodation (⊕ ciliary muscle).
• Exocrine glands→ ↑ All secretions (except milk1).
• Vascular endothelium → Nitric oxide (NO) release → VD → ↓ BP.

II. Nicotinic receptors (excitatory):

(ligand-gated Na+ /K ion channels)

• Neuronal (NN) : in autonomic ganglia, presynaptic on motor nerves & in

adrenal medulla → catecholamines release.
• Muscle (NM)→ skeletal muscle depolarization → contraction.

1
Under control of prolactin & oxytocin.
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 Autonomic Pharmacology 

Classification of Cholinomimetics

I. Directly acting (on cholinergic receptors) II. Indirect

Choline
A. Choline Esters Esterase
- 4ry drugs → low lipid solubility & poor CNS access. Inhibitors
.
- Not hydrolysed by ChE → more stable than Ach: e.g. (ChEIs)
.
Bethanechol: used in urinary retention & paralitics ileus

B. Natural Alkaloids
• Pilocarpine: 3ry drug; selective M3 agonist on:
a. Eye: Miotic …………..
b. Exocrine glands: ↑ secretion → used in dryness of
mouth & eye. sjogeren syndrome

C. Cevemiline
• Selective M3 agonist → used in dryness of mouth
(Xerostomia) & eye

Xerostomia (Dry Mouth)

- Dry mouth can either due to Diseases (e.g. DM, HIV, cancer), Drugs or aging.
- Drugs that cause xerostomia include atropine, drugs with atropine-like
action, diuretics, antihypertensive (α-methyldopa), Tizanidine.
- Xerostomia can increase the risk for caries and periodontal disease.
Management (aim at ↑ secretion)
1- Cholinomimetics: Pilocarpine and Cevemiline.
2- Saliva substitutes: mouth wash or spray and frequent small sips of water
3- Chewing gums
4- ↑↑ intake of water, oral hygiene
5- Treatment of the cause
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 Autonomic Pharmacology 

CHOLINE ESTERASE INHIBITORS

ChEIs
Mechanism of Action
• ChEIs act indirectly by inhibiting choline esterase → accumulation of ACh.
• Neostigmine has also direct effect on Nm receptors at NMJ.

Individual ChEIs
1. Edrophonium (weak, short-acting, 2-10 min - reversible)
• Binds electrostatically to the anionic site of enzyme with rapid hydrolysis.
2. Carbamate Esters (medium-duration, 3-4 hours- reversible)
• The carbamyl group binds covalently to esteratic site of enzyme (active site)
→ carbamylated enzyme (covalent bond is more resistant to hydrolysis).
3. Organophosphates (very long duration - irreversible)
• The phosphate group binds irreversibly to the esteratic site of the enzyme.
• The covalent phosphorous enzyme bond is extremely stable and hydrolyzes
in water at a very slow rate (hundreds of hours).
• Ageing occurs in the phosphorylated enzyme bond within 2 minutes - 12
hours, after which recovery of enzyme cannot occur (strengthening of
covalent bond). Thus, choline esterase regenerators in organophosphate
poisoning should be given early before ageing occurs.

ACh

Organophosphates Carbamates Edrophonium

(P group) (carbamyl group)

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 Autonomic Pharmacology 

CLASSIFICATION & USES OF ChEIs

Reversible Irreversible

Simple Alcohols Organo-

Edrophonium (4ry compound) phosphates
• Short-acting. - Malathion
(Insecticides).
Carbamates - Sarin
[Link] (synthetic; stable) (Nerve gas)
• 4ry amine → poorly absorbed - cannot cross BBB - Echothiophate:
or conjunctiva. i. Antagonizes
. • Muscarinic effects: on bladder & GIT atropine after
• Nicotinic effects: ↑ skeletal muscle power fundus exam.
2. Physostigmine (natural; unstable) ii. Glaucoma
• 3ry amine→ well absorbed, crosses BBB &
conjunctiva.
• Mainly muscarinic effects:
a. Miotic: counteracts mydriatics e.g. after
fundus examination.
b. Used in atropine toxicity.

Neostigmine analogues
• Donepezil: long acting 3ry ChEI →crosses BBB → used in Alzheimer dementia.

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 Autonomic Pharmacology 

Actions of Adverse Effects

Uses
Cholinomimetics Contraindication
(CI)

1. Alzheimer
1. CNS (M1) Ach is excitatory → [Link]
• Donepezil
Convulsions
• Arousal & short term memory. (with agents that
2. Atropine toxicity
cross BBB)
• Physostigmine
2. Eye (M3)
3. Miotics: [Link]
a. Glucoma • Miosis (⊕ constrictor pupillae).
b. To counteract
• Accommodation (⊕ ciliary muscle)
mydriatics
• Pilocarpine. • Above effects → ↑ outflow of aquous
• Physostigmine humour →↓IOP.
3. Lacrimation

3. Exocrine Glands (M3) -salivation, ↑HCl → CI

• ↑ Salivary, sweat, bronchial, lacrimal & peptic ulcer

4. Dry eye &mouth
HCl secretion.
• Pilocarpine
• Cevemiline [Link]
4. Heart (M2) Cardiac arrest (→
never given IV)
• Bradycardia – AV block CI Myocardial
Infarction

5. Hair tonic 5. Vascular endothelium (M3)

• Pilocarpine 5. Bronchospasm
• Release of EDRF → VD .
CI Asthma
6. Megacolon
Bethanechol 6. Smooth muscles (M3)
• Bronchospasm. 6. ↑ Urination- diarrhea
7. Post operative
• ⊕ bladder wall & GIT motility & \ colic- N & V
Paralytic ileus
Urine retention CI: urinary or intestinal
sphincters → micturition, defecation.
• Neostigmine. obstruction (→
• Bethanechol rupture)

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 Autonomic Pharmacology 

(Sympathetic and Parasympathetic Effects on Body Tissues)

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 Autonomic Pharmacology 

Toxicity of Organophosphorus Compounds

• Organophosphorus compounds are highly lipid-soluble & are well absorbed
from all sites & cross BBB (echothiophate has 4ry N+ → ↓systemic toxicity).
• Poisoning occurs due to suicide or exposure to drugs during spraying
insecticides (parathion, malathion) or nerve gases (sarin) during war.
Acute toxicity
• Excessive muscarinic effects (see table)
• Nicotinic effects: fasciculation & flaccid paralysis.
• CNS effects: stimulation (convulsions) → depression (coma & respiratory
depression).
Death is due to respiratory failure:
- Respiratory center depression.
- Paralysis of respiratory muscles due to persistent depolarization block.
- Excessive bronchial secretions with acute pulmonary oedema.

Chronic Toxicity: chlorpyrifos & malathion→ delayed neuropathy.

Treatment of Organophosphorus Poisoning

1. Maintain vital signs:
Aspirate bronchial secretions, endotracheal intubation & artificial respiration.
2. Decontamination (to prevent further absorption):
Remove contaminated clothes - wash skin (Na hypochlorite) - gastric lavage.
3. Atropine (large doses) for CNS & muscarinic effects:
2 -5 mg/ 5 min → full atropinization (until bronchial secretions & wheezes stop).
4. Choline esterase reactivators (oximes): PAM (pralidoxime)
Regenerates choline esterase ( IV infusion as soon as possible before its ageing).
5. Diazepam: for convulsions.

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 Autonomic Pharmacology 

ANTIMUSCARINIC AGENTS

Atropine
• It is a tertiary ammonium ester of tropic acid → well absorbed from the gut if
given orally or from conjunctiva after occular instillation & can cross BBB.
Mechanism of Action
• Atropine causes reversible competitive blockade of the actions of ACh at
muscarinic receptors (nonselective for muscarinic receptors).

Pharmacological Actions
1. CNS
• Respiratory center stimulation (blocks M2 receptors) .
• Antiemetic (blocks M1 receptors in vestibular pathway).

2. Eye (effects persist for > 72 hrs)

• Mydriasis 2( paralysis of constrictor pupillae). ↓ Aquous out flow →↑
• Cycloplegia (ciliary muscle paralysis IOP → acute glaucoma
& loss of accommodation for near vision).

3. Secretions
• ↓ Salivation (→ dry mouth), ↓ lacrimation (→ dry sandy eyes).
• ↓ Sweating (→↑ body temperature) & ↓ bronchial secretions.
• Gastric secretion is least affected while milk secretion is unaffected.

4. Smooth Muscle
• GIT: relaxes wall & contracts sphincters → constipating & antispasmodic.
• Bladder neck: contraction of urinary bladder sphincter→ urine retention.
• Bronchodilation.
5. CVS: Tachycardia & Vasodilation (histamine release).

2
Passive, due to unopposed sympathetic activity on dilator pupillae
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 Autonomic Pharmacology 

Clinical Uses of Atropine & atropine Substitutes

Atropine
Some Therapeutic Uses
1. Preanesthetic medication →inhibits secretions - dilates bronchi - anti-emetic -
inhibits reflex bradycardia - stimulates respiration.
2. Heart block - bradycardia (in infarction or digitalis toxicity).
3. Organophosphate poisoning.

Atropine Substitutes
I. Scopolamine (Hyoscine): Natural atropine substitute used in:
• Vomiting of motion sickness (more effective than atropine).
• Preanesthesia in thyrotoxic & cardiac patients

II. Synthetic atropine substitutes (more selective → fewer side effects)

1. Mydriatic cycloplegics (e.g. tropicamide):
Used in fundus examination3.

2. Antisecretory antispasmodics: e.g. Hyoscine butylbromide

Antispasmodic in renal, biliary & intestinal colic & in irritable bowel
syndrome.

3. Bronchial atropine substitutes

Ipratropium (non selective M2 / M3 blocker )

• Inhaled bronchodilator (M3 blocker) and used in asthma.

• Tolerance develops due to block of vagal presynaptic M2 receptor →↑ ACh.

Tiotropium (selective M3 blocker)

• Long acting (once/d) & No block to M2 receptors → No tolerance.

3
shorter acting than atropine → action is easier to reverse.
Mydriatics are required for fundus examination; miotics are given later to antagonize their effect
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 Autonomic Pharmacology 

Adverse Effects of atropine → poisoning (Contraindications ; CI)

[Link], restlessness → hallucinations, delirium & mania→ Mad as a hen.
2. Dry mouth and skin →Dry as a bone.
3. Hyperthermia (complete skin dryness) →Hot as a hare.
4. Vasodilation & flushing →Red as a beet.
5. Tachycardia.
6. Blurred vision - photophobia→ Blind as a bat.
7. Acute glaucoma in patients with narrow anterior chamber (CI: glaucoma).
8. Urine retention in old patients with enlarged prostate (CI: enlarged prostate).
9. Constipation.
Treatment of Atropine Poisoning
• Gastric lavage & cooling blankets for hyperthermia in children (not aspirin).
• Physostigmine (antagonizes central & peripheral effects).
• Diazepam: to control CNS excitement.

Drugs with Atropine-Like Action

™ Antihistamines (1st generation).
™ Antidepressants as TCAs
™ Pethidine.
™ Atropine substitutes.

Therapeutic Uses of Anticholinergic Drugs in Dentistry

1. ↓ Bronchial secretions during general anaethesia
2. ↓ Salivation during dental procedures & Sialorrhea (excess salivary flow)

Sailorrhea: may be due to disease e.g. stomatitis, facial palsy or drug-induced

e.g. mercurial, iodide, pilocarpine, neostigmine, expectorants
Treatment of sailorrhea:
- Atropine and atropine substitutes
- Antihistamine e.g. promethazine (it also induces sedation)
- Determination and removal of the cause
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 Autonomic Pharmacology 

SPASMOLYTICS
• Spasmolytics are drugs that reduce muscle tone with minimal effect on active
contractions.
Central
Causes of spasticity (uses of spasmolytics)
1. Central causes4
• Cerebral palsy - stroke (hemiplegia). Spinal
cord
• Multiple sclerosis - spinal cord injury Ia nerve fiber

2. Local causes: Muscle trauma – inflammation

3. Low back pain.
4. Drug induced: malignant hyperthermia.
Muscle
Classification of spasmolytic drugs
A- Centrally Acting
i. Diazepam:
Mechanism: GABA-A modulator used in most causes of
spasticity.
Side effects: sedation & tolerance.
i. Baclofen:
Mechanism: GABA- B agonist at spinal synapses.
Uses: multiple sclerosis & spinal cord injuries.
Side effects: Drowsiness (sedation less than diazepam) and
increase seizure activity in epileptic patients → withdrawal
must be very slowly.
N.B. Baclofen reduces pain perhapse by inhibiting the release of substance P
in the spinal cord.

4
Upper motor neuron lesion, with damage to descending pathways in the spinal cord →
hyperexcitability of the alpha motoneurons in the cord.
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 Autonomic Pharmacology 

iii. Tizanidine :
Mechanism: α2 agonist→ ↑ presynaptic inhibition of motor
neurones in the cord.
Uses: used in multiple sclerosis or after stroke.
Side effects: drowsiness, hypotension, dry mouth, and
asthenia.
N.B. Tizanidine also inhibits nociceptive transmission in the spinal cord.
iv. Orphenadrine:
Mechanism: It acts in the brainstem
Uses: Acute muscle spasm due to trauma or strain
Adverse effects: anticholinergic side effects & sedation.

B- Peripherally acting
i. Dantrolene
Mechanism: Inhibits Ca2+ release from the
sarcoplasmic reticulum in skeletal muscle.
Uses: Malignant hyperthermia.
Adverse effects: Generalized muscle weakness,
sedation, and occasionally hepatitis.
N.B. Marked muscle weakness →limits its use.
ii. Botulinum toxin:
Mechanism: It inhibits ACh release
Uses: Locally in
- Cosmetic therapy for wrinkles.
-Generalized spastic disorders e.g. cerebral palsy.
Adverse effects:
- Paralysis of the wrong muscle group
- Allergic reaction
- Dry mouth

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