CHOLINERGIC DRUGS

Tatyana Voyno-Yasenetskaya
312-996-9823 [email protected]

Neurotransmitter Acetylcholine

• Preganglionic synapses of
both sympathetic and
parasympathetic ganglia
• Parasympathetic
postganglionic
neuroeffector junctions
• All somatic motor end-
plates on skeletal muscle

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 Generalized Cholinergic Junction

m2 m4 m1 m3 m5
Receptor

Gi Go Gq/11, G13

PLC
G protein coupling AC
and intracellular DAG IP3
mediators
cAMP Small G proteins
PKC

GIRK channels, K+

Depolarization
Hyperpolarization (heart)
Electrical, secretory Postsynaptic excitation
Cardiac inhibition
and mechanical Smooth muscle contraction
cellular responses Presynaptic inhibition
glandular secretion
Antagonism of smooth muscle relaxation
Presynaptic inhibition

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 Different functions of muscarinic
receptors
• M1(-/-) mice - modulate neurotransmitter signaling in cortex and
hippocampus
• M2(-/-) mice - mediate muscarinic agonist-induced bradycardia,
tremor, hypothermia, and autoinhibition of release in several
brain region
• M3(-/-) mice- are involved in exocrine gland secretion, smooth
muscle contractility, pupil dilation, food intake, and weight gain
• M4(-/-) mice - dopamine activity in motor tracts and act as
inhibitory autoreceptors in striatum
• M5(-/-) mice - required for cholinergic dilation of cerebral blood
arteries

RESPONSES MEDIATED BY
MUSCARINIC RECEPTORS
HEART Atria Heart rate
A-V node A-V nodal conduction

Contraction of sphincter muscle of iris

EYE and ciliary muscle

Tone, motility, and secretion

GASTROINTESTINAL
Relaxation of sphincter
URNARY BLADDER

SECRETORY GLANDS Secretion

Sweat, bronchial, salivary glands

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 ION-CHANNEL-LINKED RECEPTOR

Nicotinic Mechanism - direct coupling of the nicotinic receptor to the

opening of ion channel selective for sodium and potassium. When the
receptor is activated, the channel open and depolarization of the cell
results. Nicotinic receptors are heteropentamrers consisting of α (α2−
α10), and β (β2−β4), subunits.
nAChR allow Na+, K+, and Ca2+ transfer

Different functions of nicotinic receptors

1. α3(-/-) mice, die at birth

2. α5(-/-) mice, impairment of cardiac
parasympathetic ganglionic transmission
3. α7(-/-) mice - nicotine-induced
desensitization of ionic currents
4. β2(-/-) mice - learning, memory, nicotine-
mediated antinociception

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 Nicotinic Receptors and Brain
disease
• Tourette’s syndrome
• Autism
• Schizophrenia
• Depression
• Attention deficit hyperactivity disorder
• Alzheimer’s disease
• Aging
• Tobacco dependence
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RESPONSES MEDIATED
BY NICOTINIC RECEPTORS

AUTONOMIC
Depolarization
GANGLIA
ADRENAL MEDULLA Secretion of epinephrine

NEUROMUSCULAR Depolarization of motor end-

JUNCTION plate

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 CHOLINOMIMETIC DRUGS

Direct-acting Indirect-acting

Receptor agonists Cholinesterase inhibitors

Carbamates Phosphates
PHYSOSTIGMINE ISOFLUROPHATE
NEOSTIGMINE Antidote
Choline esters Alkaloids PYRIDOSTIGMINE PRALIDOXIME
ACETYLCHOLINE EDROPHONIUM
PILOCARPINE
BETHANECOL

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Chemical structures of choline esters currently

in clinical use

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 PHARMACOLOGICAL PROPERTIES
OF CHOLINE ESTERS

Choline ester Susceptibility Carduovascu GI GU Eye Antagonism

to lar by atropine
cholinesterase

Acetylcholine
+++ ++ ++ ++ + +++
Metacholine
+ ++++ +++ ++ + +++
Carbachol
- + +++ +++ ++ +
Bethanecol
- + +++ +++ ++ +++
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Pharmacological Properties
Cardiovascular System
1. Vasodilatation
ACh produces dilatation of essentially all vascular beds, including the
pulmonary and coronary vascular beds.
Mechanism - stimulation of M3 receptor on endothelial cells releases
endothelium-derived relaxing factor, or nitric oxide.
Coronary vasodilatation may be elicited by cardiovascular reflexes or by direct
electrical stimulation of the vagus.

2. Decrease in cardiac rate (the negative chronotropic effect)

Cholinergic stimulation affects cardiac function directly and by inhibiting the effects of
adrenergic activation.

3. Decrease in the rate of conduction in the specialized tissues of the sinoatrial

(SA) and atrioventricular (AV) nodes (the negative dromotropic effect)

4. Decrease in the force of cardiac contraction (the negative inotropic effect).

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 Gastrointestinal System
•increases in tone, amplitude of contractions, and peristaltic activity of the stomac
and intestines
•enhances secretory activity of the gastrointestinal tract.

Urinary Tract
•increase ureteral peristalsis, contract the detrusor muscle of the urinary bladder,
•increase the maximal voluntary voiding pressure, and decrease the capacity
of the bladder.

Other effects
•Stimulation of secretion by all glands that receive parasympathetic innervation
(lacrimal, tracheobronchial, salivary, digestive, and exocrine sweat glands ).
•Respiratory system - increased tracheobronchial secretion
•and bronchoconstriction
•Eye - miosis
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Therapeutic Uses
Bethanechol chloride (carbamylmethylcholine chloride;
URECHOLINE,

* Stimulant of the smooth muscle of the gastrointestinal tract and,

particularly, the urinary bladder.
- postoperative abdominal distension and gastric atony and retention or
gastroparesis.
- urinary retention and inadequate emptying of the bladder when organic
obstruction is absent, as in postoperative and postpartum urinary retention
and in certain cases of chronic hypotonic, myogenic, or neurogenic
bladder.
* alternative to pilocarpine to promote salivation
Xerostomia dryness of the mouth.
Sjogren syndrome -immunologic disorder with destruction of the
exocrine glands leading to mucosal dryness

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 • Carbachol usually is not employed for these purposes
because of its relatively larger component of nicotinic
action at autonomic ganglia.
• The unpredictability of the intensity of response has
virtually eliminated the use of methacholine or other
cholinergic agonists as vasodilators and cardiac
vagomimetic agents.
• Methacholine chloride (acetyl-b-methylcholine chloride;
PROVOCHOLINE) may be administered for diagnosis
of bronchial hyperreactivity and asthmatic conditions.

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Precautions, Toxicity, and

Contraindications.
•ACh and its agonist analogs should be administered only by the oral or subcutaneous
route for systemic effects; they also are used locally in the eye.

•Antidote - atropine.

•Epinephrine may be used to overcome severe cardiovascular or bronchoconstrictor

responses.

•Among the major contraindications to the use of the choline esters are asthma,
hyperthyroidism, coronary insufficiency, and acid-peptic disease.

•Bronchoconstrictor action could precipitate an asthmatic attack

•Hyperthyroid patients may develop atrial fibrillation.

•Hypotension induced by these agents can severely reduce coronary blood flow,
especially if it is already compromised.

•The gastric acid secretion produced by the choline esters can aggravate the symptoms of
acid-peptic disease.

•Other possible undesirable effects of the cholinergic agonists are flushing, sweating,
abdominal cramps, a sensation of tightness in the urinary bladder, difficulty in visual
accommodation, headache, and salivation. 18

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 CHOLINOMIMETIC NATURAL
ALKALOIDS AND SYNTHETIC
ANALOGS

The three major natural alkaloids in this group pilocarpine, muscarine,

and arecoline have the same principal sites of action as the choline
esters.

Muscarine acts almost exclusively at muscarinic receptor sites, their

classification as such being derived from this fact.

Arecoline also acts at nicotinic receptors.

Pilocarpine has a dominant muscarinic action, but it causes anomalous

cardiovascular responses, and the sweat glands are particularly sensitive
to the drug.

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 CHOLINOMIMETIC DRUGS

Direct-acting Indirect-acting

Receptor agonists Cholinesterase inhibitors

Carbamates Phosphates
PHYSOSTIGMINE ISOFLUROPHATE
NEOSTIGMINE Antidote
Choline esters Alkaloids PYRIDOSTIGMINE PRALIDOXIME
ACETYLCHOLINE EDROPHONIUM
PILOCARPINE
BETHANECOL

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ACETYLCHOLINESTERASE INHIBITORS
OR INDIRECT ACTING AGONISTS

O O
+
H3C–C–O–CH2 –CH2– N–(CH3)3+ H2O H3C–C + HO–CH2 –CH2– N–(CH3)3 +H+
Acetylcholine AcetateO- Choline

Acetylcholinesterase 320 kDa enzyme

Cleaves 25,000 molecules of Ach per second

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 Reversible Inhibitors Irreversible Inhibitors
Organophosphates
Water-soluble Lipid-soluble

Edrophonium Isoflurophate
Neostigmine
Pyridostigmine
Physostigmine

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MECHANISM OF ACTION
Both water-soluble and lipid soluble inhibitors bind
acetylcholinesterase and phosphorylate its active site, thus preventing enzyme
from binding and hydrolysis of acetylcholine.
Water-soluble inhibitors are hydrolyzed within 2-8 hours.
Lipid-soluble inhibitors form stable complex with enzyme
and are released over periods of days to weeks. 23

Clinical Applications
DRUG APPLICATION ACTION
Physostigmine Glaucoma Amplifies effect of Ach

Neostigmine Myastenia gravis, reversal Amplifies effect of Ach

Pyridostigmine of neuromuscular block
Edrophonium
Isophlurophate Glaucoma Amplifies effect of Ach

Donepezil Alzheimer’s disease Amplifies effect of Ach

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 Effects of Severe
Acetylcholinesterase Inhibition
• GI - Diarrhea, urination, vomiting, salivation - all due to increased
tone and motility
• Eye - Miosis
• Respiratory - Bronchoconstriction, increased bronchial secretion
• CNS - Tremor, anxiety, convulsions, coma
• Skeletal muscle - Fasciculation
• Cardiovascular - Hypotension

• DUMBELS Syndrome - Diarrhea, Urination, Miosis,

Bronchoconstriction, Excitation (of skeletal muscle and CNS),
Lacrimation, Salivation, and Sweating

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Intermediate Syndrome
• Described in mid-1980, IMS follows
organophosphorus insecticide poisoning
• Occurs in 20% of patients
• Develops 2-4 days after exposure when acute
cholinergic syndrome is no longer obvious
• Weakness of muscles is the main symptome
• Some patients require ventilatory care up to 21
days

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DRUG TREATMENT OF POISONING WITH
ORGANOPHOSPHATE INSECTICIDES

• Anti- muscarinic - Atropine - reduces effect

of Ach
• Cholinesterase reactivator - Pralidoxime,
induces dephosphorylation and reactivation
of acetilcholiesterase

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SARIN, SOMAN – chemical warfare

• Developed in late 1930s as a candidate

pesticide
• Was used by Aum Shinrikyo in 1994, 600
people were exposed, 7 people died

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Agonists of Nicotinic Receptors
• α7 selective agonist - potential candidate
for treatment of schizophrenia
• Treatment of dementia
• Alzheimer’s disease

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CHOLINERGIC ANTAGONISTS

MUSCARINIC NICOTINIC
ANTAGONISTS ANTAGONISTS

GANGLIONIC NEUROMUSCULAR
BLOCKING AGENTS BLOCKING AGENTS

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 Location of muscarinic
receptors subtypes
• M1 is located in central nervous system
• M2 is located in the myocardium, smooth
muscles, some neuronal sites
• M3 is common on effector cell membranes,
such as glandular and smooth muscle cells

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MUSCARINIC ANTAGONISTS

Atropine and Scopolamine are belladonna alkaloids

(Atropa belladonna), competitive antagonists of
Muscarinic receptors

Atropine and scopolamine differ in their ability to affect CNS

Atropine in therapeutic doses has almost no effect
Scopolamine has significant effect even in low doses
The reason is the greater permeability of scopolamine through blood-brain barrier
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 Mechanism of action
• Blocks muscarinic receptors
• Salivary, bronchial, and sweat glands are
most sensitive to atropine
• Smooth muscle and heart are intermediate
in responsiveness

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EFFECTS OF MUSCARINIC
BLOCKING DRUGS
Drowsiness, antimotion sickness action, antiparkinson
CNS action, amnesia, delirium
Cycloplegia*, mydriasis, reduction of lacrimal secretion
EYE (sandy eyes)
Bronchodilation
BRONCHI
Relaxation, slowed peristalsis
GI
Relaxation of bladder wall, urinary retention
GU
Initial bradycardia, then tachycardia
HEART
Decrease of secretion
GLANDS
*Cycloplegia - spasm of accommodation, weakening of contraction of ciliary muscle

**Initial bradycardia is from block of M2 receptors in the heart. Tachycardia is from blocking of vagus.
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 CLINICAL APPLICATION OF
ANTIMUSCARINIC DRUGS
ORGAN DRUGS APPLICATION
CNS Benztropine Treat the manifestation of
Parkinson's disease
Scopolamine Prevent or reduce motion
sickness
EYE Atropine Produce mydriasis and
cycloplegia
BRONCHI Ipratorium Bronchodilate in asthma
GI Methscopolamine Reduce transient motility - used
in combination with other
antiulcer drugs
GU Oxybutinin Treat transient cystitis and
postoperative bladder spasms

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Toxicity of antimuscarinic
drugs
"DRY AS A BONE, RED AS A BEET, MAD AS A HATTER"

1. "Dry as a bone" is a result of decreased sweating, salivation, and lacrimation.

2. "Red as a beet" is a result of dilation of cutaneous vessels of the arms, head, neck,
and trunk - "atropine flush".
3. "Mad as a hatter" is a result of CNS effects, including sedation, amnesia, delirium
or hallucination.

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 NICOTINIC ANTAGONISTS

GANGLIONIC BLOCKERS

• Interfere with postsynaptic transmission of

Ach
• Block action of Ach on nicotinic receptors
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GANGLIONIC BLOCKING AGENTS

• Ganglionic agents block nicotinic receptors on

the post-ganglionic or neuromuscular junctions
• Different subtypes of nicotinic receptors exist
at ganglia and neuromuscular junctions
• Trimethaphan and mecamylamine are
competitive antagonists of ACh

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 Effects of ganglion-blocking drugs
ORGAN EFFECT
EYE Moderate mydriasis and cycloplegia
GI TRACT Reduced motility and constipation
GU TRACT Reduced contractility of the bladder
VESSELS Reduction of arteriolar and venous tone;
decreased blood pressure
GLANDS Reduction of salivation, lacrimation, sweating,
and gastric secretion

Ganglion-blocking drugs are not used due to severe adverse effects. They were
important historically for the beginning of successful treatment of hypertension.
They were used in hypertension is for initial control of blood pressure
in patient with acute dissecting aortic aneurysm.
The reasons are:
1) reduce blood pressure
2) inhibit sympathetic reflexes and thereby reduce the rate of pressure rise at the site of the tear
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NEUROMUSCULAR BLOCKING
AGENTS

EPP -end-plate potential

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 Neuromuscular blocking drugs

Nondepolarizing Depolarizing
(succinylcholine)

Long duration Short duration

(vecuronium,
(tubocurarine)
pancuronium)

Neuromuscular blocking drugs are used

to induce complete skeletal muscle relaxation in surgery

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MECHANISMS OF BLOCKADE

NONDEPOLARIZING DRUGS - bind to nicotinic receptor

and competes with acetylcholine.
DEPOLARIZING DRUGS - acts as nicotinic agonist and induces depolarization.
Because skeletal muscle tension can not be maintained without
repolarization/depolarization of the endplate, continuous depolarization results
in muscle relaxation.
DECREASE IN ACh RELEASE - botulinum toxin

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 TOXICITY
1. RESPIRATORY PARALYSIS - neuromuscular blockers induce a respiratory paralysis.
If mechanical ventilation is not provided, the patient will asphyxiate.

2. MALIGNANT HYPERTHERMIA - Malignant hyperthermia susceptibility, an

autosomal dominant disorder of skeletal muscle, is one of the main causes of death due to
anesthesia. Depolarizing neuromuscular blocking drugs (succinylcholine) can trigger
malignant hyperthermia.

Malignant hyperthermia is a result of excessive release of Ca2+ from sarcoplasmic reticulum.

The clinical features of malignant hyperthermia are hyperthermia, metabolic acidosis,
tachycardia, accelerated muscle metabolism and contructures.
Genetic basis for the disease is a mutation in Ca-releasing channel - ryanodine receptor
DANTROLENE is used to treat malignant hyperthermia. Dantrolene blocks release from the
sarcoplasmic reticulum, reduces heat production and muscular tone.

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Selective nicotinic receptor

antagonists
• Depression, bipolar disorder

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