Cholinergic agonists and Acetylcholinesterase inhibitor

Cholinomimetics definition

Ligand that works to mimic Acetylcholine

First category of Cholinomimetics Direct acting parasympathomimetic

Direct acting parasympathomimetic

• Receptor agonists

  • Muscarinic

  • Nicotinic

Increase action by binding to the receptor

Indirect-acting parasympathomimetic (cholinesterase inhibitors)

• Cholinesterase inhibitors

  • Inhibit enzyme that breaks down acetylcholine

Increase action by inhibit the enzyme

Muscarinic mechanism of action (after bind with cholinmimetics)

• Muscarinic transmission to the SA node in the heart

• ACh released from varicosity of a postganglionic cholinergic axon interacts with SA node cell muscarinic receptor, linked via G_i/_o to K⁺ channel opening causing hyperpolarization, and to inhibition of cAMP synthesis.

• Reduced cAMP shifts voltage-dependent opening of pacemaker channels to more negative potentials, and reduces the phosphorylation and availability of L-type C²⁺ channels

• Released ACh also acts on an axonal muscarinic receptor to cause inhibition of ACh release (autoinhibition)

ACh leads to K channel opening, positive K leak out, cell become negative making it hard to reach electrical threshold required to fire a heart beat. 

It shut down the production of cAMP, a key messenger molecule that tells the heart to speed up. Leading to the pacemaker channel needs more negative charge to open, delays the start of next electrical pulse

cAMP usually activates C++ channel through phosphorylation, by inhibiting, the cell reduces the availability of these calcium channels, since calcium is necessary for the rapid upstroke of pacemaker’s electrical signal, the signal becomes weaker and slower to develop

Autoinhibition is the safety valve, some of the ACh travels back to receptors on the axon itself, acts as a negative feedback loop, it signals the nerve to stop releasing so much ACh, preventing the braking effect from becoming too extreme and stopping the heart entirely. 

Nicotinic signaling for contraction

1. Nicotinic transmission at the skeletal neuromuscular junction. 

2. ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic protection. 

3. The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. 

4. Acetycholinesterase in the extracellular matrix hydrolyzes ACh.

Nicotine - Chlinomimetics

Numerous brand names, N_N subunits: alpha4, alpha7, beta2. Direct cholinomimetics.

Nicotine mechanism of action

Brain:  Dopaminergic neurons release dopamine leading to euphoria, dependence

• Stimulant (locus ceruleus) and reward (limbic) effects

Chromaffin cells (stimulate by nicotine) in adrenal medulla release epinephrine leading to vasoconstriction, increased, blood pressure, increase heart rate, and increase blood glucose

Nicotine PK profile

A: Mucosal/transdermal - slow absorption

D: 2-3 L/kg of distribution

M: Hepatic, cotinine primary metabolite, over 15 metabolite

E: 10% excreted unchanged in urine

Cholinergic effects

• S - Salivation

• L - lacrimation

• U - urination

• D - diaphoresis (sweating) / defecation

• G - GI upset

• E - Emesis (vomiting)

• M - miosis (pin-point pupils)

• B - bradycardia

Varenicline

Direct cholinomimetics. Brand name: Chantix for smoking cessation and Tyravaya nasal spray for dry eye disease.

Varenicline PD/MOA

PD: Particle nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain.

MOA: Partial agonist of nicotinic acetylcholine receptors producing modest dopamine levels but blocking nicotine.

Varenicline PK

• A: None

• D: Protein

• M: Minimal <10%

• E: 92% excreted unchanged in urine, glomerular filtration and active tubular secretion

Varenicline side effects

• N/V, abnormal dreams, depressed mood, HA, insomnia, irritability

Bethanechol

Direct agonist. Brand name Urecholine (urinary acetycholine).

Bethanechol PD/MOA

PD: 

• stimulation of PNS; direct action on muscarinic receptors (M3)

MOA:

• Increase bladder muscle (detrusor) tone causing contraction which initiate urination

Bethanechol PK

• A - poor onset of 30 minutes, max effect 60-90 minutes, duration for 2 hours

• D - charged quaternary amine, therefore does not cross BBB

• M: Not metabolized by Acetylcholinesterase

• E: ?

Bethanechol indication

Neurogenic bladder, acute postoperative and postpartum non-obstructive urinary retention

Bethanechol contraindication

Strength or integrity of the GI or bladder wall is questionable

Bethanechol side effects

Abdominal pain or camps, colicky pain (sudden abdominal pain), belching (gas, burping), hypersalivation, diarrhea, flatulence, nausea, vomiting, and borborygmi (stomach gurgling).

Carbachol

Direct agonist, Isopto carbachols (gtts), Miostat (intraocular inj.)

Carbachol PD/MOA

PD:

• Stimulation of PNS; direct action on muscarinic receptors (M1, M2)

MOA:

• Constriction of the iris and ciliary body occur, subsequent decrease in intraocular pressure

Carbachol PK

Unlikely to across BBBC

Carbachol indication

Use for miosis (pin-point pupil) during cataract surgery and reduce intraocular pressure following cataract surgery

Carbachol side effect

Transient ocular irritation, blurred vision