Muscarinic Agonists (cholinergics)

MOA:
 Binds to muscarinic receptors and activates them.
 Turns on the parasympathetic nervous system
o Decreased heart rate
o Increased salivation/secretions (Gastric and Bronchial)
o Bronchoconstriction
o Pupillary constriction
o Increased GI motility
o Urinary emptying
o Bowel emptying
o Generalized sweating

Medications
 Bethanechol (Urecholine, Duvoid)
à MOA
a. Binds to muscarinic receptors directly and activates them.

à Therapeutic Uses
a. ONLY approved use is for urinary retention
i. Increases bladder emptying capability
b. There are studies for gastroesophageal reflux treatment

à Adverse Effects
a. Hypotension (secondary to bradycardia and vasodilation)
b. Excess salivation
c. Excessive bronchoconstriction
d. Over motile GI tract: Abdominal cramps, diarrhea, and increase in gastric acid

à Contraindications
a. Hyperthyroidism: can cause tachycardia and dysrhythmias.
b. Asthma: latent or active. Bronchoconstriction exacerbates asthma effects.

 Cevimeline (Evoxac)
à MOA
a. Binds to muscarinic receptors on the intact salivary glands and increases
secretions in the mouth and eyes and increases tear production.

à Therapeutic Uses
a. Xerostomia (dry mouth)
b. Dry eyes

à Adverse Effects
 a. Same as bethanechol.

à Contraindications
a. Iritis
b. Glaucoma (increases IOP)
c. Beta blocker use (they both increase cardiac depression)

 Pilocarpine (Salagen)
à MOA
a. Helps decrease IOP in those with glaucoma by binding to muscarinic receptors in
the iris causing it to contract and push out aqueous humor.
à Therapeutic uses
a. Glaucoma
b. Xerostomia
à Adverse effects
a. Low doses= sweating
b. High doses= same as bethanechol

Muscarinic Agonist Poisoning

Causes: Mushrooms & overuse of direct muscarinic agonists and anticholinesterase inhibitors.

à Signs and Symptoms

a. Profuse salivation
b. Tearing (lacrimation)
c. Diarrhea
d. Bradycardia
e. Hypotension
f. Visual disturbances
g. Bronchospasm
à Treatment
a. Oxygen administration
b. Increase fluid intake
c. Safe surroundings
d. EKG monitoring

ANTIDOTE
ATROPINE (muscarinic antagonist)
Prevents receptor activation by blocking the muscarinic receptor.
Produces its effects by not allowing agonists/Ach to bind.
Muscarinic Antagonists (anticholinergics)
MOA:
 Binds and blocks the muscarinic receptors resulting in NO ACTIVATION.
 Due to no activation, does the opposite of the muscarinic agonists.
o Increased heart rate
o Decreased salivation/dry mouth
o Bronchodilation
o Pupillary dilation
o Decreased GI motility
o Urinary retention
o Constipation
o Anhidrosis (decreased/absent sweat production)

Medications
 Atropine (muscarinic agonist poisoning antidote)
à MOA
a. Blocks the muscarinic receptors leading to no activation and opposite effects of
agonists.
à Therapeutic Uses
a. Prevents reduction of heart rate during surgery; bradycardia
b. Eye exams (paralyzes ciliary muscles)
c. Muscarinic poisoning

à Adverse Effects
a. Dose dependent!!!!!
 Dry mouth
 Blurred vision
 Increased IOP
 Urinary retention
 Constipation
 Anhidrosis
 Tachycardia

à Contraindications
a. Glaucoma
b. IOP

 Oxybutynin
 MOA
a. Blocks the muscarinic receptors leading to no activation and opposite effects of
agonists.

 Therapeutic Uses
a. Only used for an overactive bladder (decreases urinary emptying)
  Adverse Effects
a. Same as Atropine

Considerations
à Low bioavailability due to high first pass metabolism
à Short half life
à Lipid soluble and can pass BBB

 Mirabegron BETA 3 AGONIST, NOT AN ANTICHOLINERGIC, BUT ACTS

THE SAME WAY
à MOA
a. Binds to Beta 3 receptors and relaxes the detrusor muscle which increases
filling and decreases frequency and urgency.

à Therapeutic Uses
a. Given to those who cannot take anticholinergic medications
b. Indicated only for the use of an OAB

à Adverse Effects
a. Increased heart rate
b. Increased blood pressure

 Solifenacin & Tolterodine

à Primarily metabolized by the liver and excreted by the kidneys, so do not give if patient
has liver or kidney impairment.
à Solifenacin adverse effects can also include angioedema and dysrhythmias.
à Tolterodine is only approved for OAB use.

Muscarinic Antagonist Poisoning

Causes: no binding of agonists to the receptors causing a lack of parasympathetic activation.

à Signs and Symptoms

a. Dry mouth
b. Blurred vision
c. Photophobia
d. Hyperthermia
e. Delirium and hallucinations
f. Respiratory depression
g. Hot, dry, flushed skin

à Treatment
a. Administer an antidote
b. Minimize muscarinic antagonist absorption by giving activated charcoal
 ANTIDOTE
Physostigmine
Cholinesterase inhibitor which blocks acetylcholinesterase from
breaking down Ach which increases its levels. It competitively binds
against the muscarinic antagonist.

Cholinesterase Inhibitors (Reversible and Irreversible)

MOA: inhibits acetylcholinesterase and in doing so increases the amount of Ach available for
binding.
ACTS SIMILAR TO A MUSCARINIC AGONIST!

à Reversible
o All of the medications listed below
à Irreversible
o Insecticides
o Toxic
o Only approved use is for glaucoma
o Responses are long!

Medications
Neostigmine
à MOA
a. Reversible cholinesterase
b. Binds to cholinesterase and prevents it from binding to Ach to degrade it which
increases the amount of Ach available to activate receptors.
c. Neostigmine lasts as long as it takes for cholinesterase to break it down.

à Therapeutic Uses
a. Myasthenia gravis
b. Reduce effects of neuromuscular blocking agents/ treats overdose
c. Treats muscarinic antagonist poisoning

à Adverse Effects
a. Similar to muscarinic agonist
b. In toxic amounts can cause too much Ach which depolarizes and causes a
neuromuscular blockade causing respiratory depression which can be fatal.

Physostigmine
à Treats Atropine overdose (Muscarinic antagonist poisoning)
à Same MOA and Adverse Effects as neostigmine.
à PREFERRED OVER NEOSTIGMINE BECAUSE IT READILY CROSSES THE BBB
AND REVERSE MUSCARINIC BLOCKADE IN THE CNS TOO.
Pyridostigmine
à ANTIDOTE FOR NONDEPOLARZING MUSCULAR BLOCKADE
à Same MOA and Adverse Effects as neostigmine.

Contraindications
a. Those taking succinylcholine
i. Increases the time succinylcholine is in the body. It is normally a
medication that is out of your system in 10 minutes. However, since it is
broken down by pseudocholinesterase, and you are inhibiting it, it stays in
your system for longer. This medication could prolong paralysis in these
patients if they are given these medications at the same time.

CHOLINERGIC CRISIS/MYASTHENIA GRAVIS CRISIS/IRREVERSIBLE CHOLINESTERASE

INHIBITOR EXPOSURE
What is it?
Overdose with cholinesterase inhibitors which increases the amount of Ach too much causing
depolarizing and paralysis of breathing muscles!

S&S
 Diarrhea/diaphoresis
 Urination
 Miosis
 Bronchospasm/bronchorrhea
 Emesis
 Lacrimation
 Salivation

Treatment
 Muscarinic effects are treated with IV ATROPINE
 CNS respiratory depression is treated with mechanical ventilation and oxygenation
 Give medication to reverse inhibition of cholinesterase
Neuromuscular Blocking Agents
MOA: block the NICOTINIC (M) receptors which control skeletal muscle which causes them to
not contract. leads to flaccid paralysis.

Medications
DEPOLARIZED
what does that mean?
 Binds to nicotinic receptors on the motor end plate and stays bound which causes a
moment of contraction and then flaccid paralysis.

Succinylcholine

 MOA
a. Quickly finishes its effects due to the presence of pseudocholinesterase
b. Peaks at 1 minute and is done in 4-10
c. Do not give to patients on cholinesterase inhibitors

 Therapeutic Effects
à Used primarily for muscle relaxation during endotracheal intubation
à Sometimes used off label to treat muscle contractions during electroconvulsive therapy.
à Short duration, so not used in prolonged procedures.

 Adverse Effects

a. Prolonged apnea in patients with low pseudocholinesterase activity (patient stays paralyzed
for longer resulting in the apnea)

b. Malignant Hyperthermia
à Muscle rigidity caused by extreme body temperature elevation.
à Caused by excessive and uncontrolled metabolic activity in the muscle
I. Signs and Symptoms
i. Increased body temperature
ii. Increased release of calcium
iii. Unstable BP
iv. Dysrhythmias

II. Treatment:
i. Discontinue succinylcholine
ii. Cool the patient down with IV saline or ice packs
iii. Give IV Dantrolene
Antidote: Dantrolene
How does it work?
Stops heat generation by acting directly on skeletal muscle to reduce its metabolic activity.

c. Post-operative muscle pain

d. Hyperkalemia

NONDEPOLARIZED
what does that mean?
 Competitively compete with Ach to bind to the nicotinic (M) receptors on the motor end
plate.
 Skeletal muscle cannot contract if Ach cannot bind. Causes flaccid paralysis

What are these medications used for?

 Muscle relaxation
 First to become paralyzed are the eyelids and muscles of
mastication
 Limbs, abdomen, and glottis are next
 Intercostal muscles and diaphragm are last to be affected.
à Muscle relaxation during surgery, endotracheal intubation, and mechanical ventilation.
Pancuronium
Eliminated by the kidneys
Vecuronium
Eliminated by the liver
Rocuronium
Eliminated by the liver
Cistatracurium
Eliminated by spontaneous degradation, ideal choice for patients with liver or kidney
dysfunction.
Atracurium
Eliminated by plasma cholinesterase, not by the liver or kidneys, so it is an ideal choice
for patients with liver or kidney dysfunction.
Histamine: lowers blood pressure

Adverse Effects
à Respiratory arrest
à Hypotension (specifically Atracurium)

Contraindications and Precautions

à Those with myasthenia gravis; can make muscle weakness worse

ANTIDOTE FOR NON-DEPOLARIZING BLOCKADE

Pyridostigmine (would not give with succinylcholine, because it would make effects
last longer)
causes Ach to build up and compete for nicotinic receptor sites causing the receptors to become
activated and a skeletal muscle contraction to be carried out.
NEUROMUSCULAR BLOCKERS OF ALL KINDS CAN HAVE DRUG-DRUG
INTERACTIONS WITH….

à CHOLINESTERASE INHIBITORS
à ANTIBIOTICS