Cholinergic agonists

steps in cholinergic transmission

1. ACh synthesis by ChAT

2. vesicular packaging of ACh

3. release of ACh from vesicles

4. postsynaptic receptors

5. degradation by AChE

6. Re-uptake of choline

vesamicol

inhibits vesicular packaging

botulinum toxin

blocks release of ACh from vesicles

AChEIs

prevent degradation and indirectly simulate AChRs

hemicholinium

inhibits re-uptake of choline

M1 receptors

location: nerves

Postsynaptic receptor mechanism: IP3, DAG cascade to increase Ca2+

M2 receptors

“Cardiac M2”

location: heart

Postsynaptic receptor mechanism: inhibition of cAMP production, activation of K+ channels, inhibition of Ca2+ channels

M3 receptors

location: glands, smooth muscle, endothelium

Postsynaptic receptor mechanism: IP3, DAG cascade to increase Ca2+

N_M

muscle type and plate receptor

location: skeletal muscle and NMJ

Postsynaptic receptor mechanism: Na+, K+ depolarizing ion channel

N_N

neuronal type, ganglion receptor

location: postganglionic cell body, dendrites

Postsynaptic receptor mechanism: Na+, K+ depolarizing ion channel

muscarinic subtypes: M1

neural, located in the brain

involved in learning and memory, implicated in Alzheimer’s disease

muscarinic subtypes: M2

heart

decreased SA node firing rate and AV node conduction velocity

muscarinic subtypes: M3

smooth muscle (contraction) and glands (secretion)

selective M3 antagonists for Tx of OAB

synthesis of EDRF, involved in vascular relaxation

cholinergic

involving the synthesis, release, or action of ACh

cholinomimetic

a drug that results in the stimulation of ACh receptors, can be direct or indirect

parasympathomimetic

any agent mimicking ACh

parasympatholytic

any agent blocking the effects of ACh

Anticholinesterase

inhibits AChE (AChEI)

anticholinergic

a drug that blocks ACh receptors, either nicotinic or muscarinic receptors. most of the time it refers to muscarinic recptors

antimuscarinic

blocks muscarinic receptors

antinicotinic

blocks nicotinic receptors

miosis

small pupil (constriction of sphincter muscle)

mydriasis

large pupil (relaxation of sphincter muscle)

bradycardia

slow heart rate

tachycardia

rapid heart rate

direct acting cholinergic agonists: choline esters

ACh, methacholine, carbachol, bethanechol

direct acting cholinergic agonists: naturally occurring alkaloids

muscarine, pilocarpine, arecoline, nicotine

ACh can act at

1. muscarinic receptors (end organs of PSNS, sweat glands of SNS, certain brain synapses)

2. nicotinic receptors (ganglia of SNS and PSNS, adrenal medulla, NMJ, certain brain synapses)

why is ACh not used clinically?

it is not selective

it is rapidly hydrolyzed

naturally occurring muscarinic agonists

ACh, muscarine, pilocarpine

ACh structure

muscarine structure

pilocarpine structure

AChEI

compete with ACh for the active site of AChE

- decrease in ACh degradation

- ACh in synaptic cleft increases

- ACh receptor binding increases

- PSNS: parasympathomimetic activity

Edrophonium

AChE-I

peripherally acting

Donepezil

brand: Aricept

AChE-I

crosses BBB - Tx Alzheimer’s

non-competitive reversible inhibitors: MOA

bind to same active site as ACh (on AChE), the drug is hydrolyzed and leads to the formation of a carbamylated enzyme

the carbamylated form of AChE is less sensitive to a second hydrolysis reaction. takes 15-30 minutes to regenerate AChE

Carbamic acid derivatives

non-competitive reversible AChE inhibitors

pyridostigmine, neostigmine, physostigmine, demecarium, ambenoium

Irreversilble AChEIs: MOA

initial hydrolysis reaction leads to formation of phosphorylated enzyme (organophosphate binds at active site)

second hydrolysis rxn cannot happen - thus the inhibition is irreversible

takes days to weeks to make new enzymes

organphosphates

echothiopate, parathion, malathion

nerve gas poisons (sarin, soman, tabun)

2-PAM

organophosphate poisoning antidote

use before aging occurs - if you wait it will not work

sarin

parathion

SLUDGE

Salivation

Lacrimation

Urination

Diarrhea

Gastric emptying

Emesis

parasympathomimetic effects

DUMBELS

Diarrhea/diaphoresis
Urination
Miosis
Bradycardia/bronchorrhea
Emesis/emptying
Lacrimation
Salivation

parasympathomimetic effects

MTWHFS

Mydriasis
Tachycardia
Weakness (muscle)
Hypertension
Fasciculations
Seizures

nicotinic agonist effects

eye - PSNS effects

miosis - constriction of pupils (sphincter muscle)

change shape of lens for near vision

increased aqueous humor outflow (helpful in glaucoma)

lacrimation

M2 effects on the heart

HR decreased

conduction velocity (dromotropy) decreased

contractile strength (inotropy) decreased

M3 effects on the blood vessels

PSNS fibers innervate muscarinic receptors only on blood vessels in the viscera

note: other vessels of the peripheral circulation have muscarinic receptors but are not innervated. They could, however, respond to circulating agonists

blood vessels: inner layer

endothelium, location of M3 receptors

blood vessels: middle layer

smooth muscle, location of adrenergic receptors

blood vessels: outer layer

collagen

endothelial regulation of nitric oxide-mediated vascular smooth muscle relaxation

- activation of M3 muscarinic receptors on the endothelial cells of blood vessels

- G_q activation increases Ca2+, which activates Ca2+ - calmodulin complex

- Endothelial nitric oxide synthase (eNOS) is stimulated to produce NO

- NO diffuses into vascular smooth muscle cells, where it activates guanylyl cyclase to produce cGMP, which causes relaxation of vascular smooth muscle

bronchomotor tone - agonist effects

major player in regulation - PSNS

contraction of bronchiolar smooth muscle and bronchoconstriction (via M3) (resistance to airflow)

pulmonary secretions - agonist effects

increased mucus secretions from epithelial cells lining the airways (via M3)

digestion - agonist effects

stimulation of salivary and gastric gland secretions

increased motility of the GI tract (increased peristalsis)

defecation - agonist effects

relaxation of sphincter muscles which line intestinal tract

detrusor muscle

forms the body of the bladder

contraction controlled by M3 receptors

relaxation controlled by beta 2 receptors

trigone sphincters

contraction controlled by alpha 1 receptors

relaxation controlled by M3 receptors

micturition

contraction of detrusor and relaxation of trigone sphincters

clinical uses - GI/GU surgical interventions

post-surgery, patients often experience atony of bladder, stomach, and/or intestines

agonists stimulate GI motility and emptying of bladder

bethanechol (urecholine)

direct cholinergic agonist

given orally or subcutaneously

induces peristaltic activity of the gut and stimulates bladder contraction

bethanechol: contraindication

peptic ulcer

urinary tract obstruction

systemic side effects are a concern

Myasthenia gravis

autoimmune disease

body produces antibodies against nicotinic receptors on skeletal muscle

muscles are unable to contract in response to the release of ACh from the motor neuron

symptoms: ptosis, diplopia, difficulty in swallowing and chewing, weakness in the extremities, breathing difficulties

edrophonium

IV administered AChE-I

very short acting

used for diagnosis of myasthenia gravis

Pyridostigmine (mestinon)

AChEI - reversible, indirect acting agonist

oral administration

slow onset of action (1-2 hours), DOA = 8-12h

useful for chronic treatment of MG

neostigmine (prostigmine)

AChEI - reversible, indirect acting agonist

oral admin

rapid onset (10-30 minutes), DOA = 2-4h

Tx MG

Presbyopia

age related blurry near vision

common, progressive condition that reduces the eyes ability to focus on near objects

Pilocarpine (Vuity)

ACh agonist

eye drops used once daily

recall PSNS actions of the eye

- contraction of the ciliary muscles - change shape of lens for near vision

- constriction of pupils (miosis)