Cholinergic/anticholinergic

Question 1

Cholinergic neurotransmission:

Answer 1

1. Choline enters axon -> Ach synthesized from choline and AcCoA via ChAT
2. AcH transported into vesicle and released via exocytosis from influx of Ca2+ (VAMPS/SNAPS fuse)
3. Ach acts on post synaptic (effect) or pre synaptic (regulate) receptors
4. Metabolized via acetylcholinesterase (AChE)

Question 2

Pro-Cholinergic:

Answer 2

Muscarinic agonists
Mimics effect of Ach at post-ganglionic receptor
o NO effect on skeletal muscle or autonomic ganglia
o Natural antagonist: belladona

Neuronal nicotinic agonists
o Mimics effect of Ach on skeletal muscle and autonomic ganglia
o Potientiallt stimulate both SANS and PANS ganglia
o NO effect on post ganglionic (muscarinic) receptors
o Natural antagonist: curare

Acetylcholinesterase inhibitors (indirect agonists)

Question 3

anti-cholinergic

Answer 3

Anti-Cholinergic:
• Muscular nicotinic antagonists
• Muscarinic antagonists

Question 4

cholinergic receptors

Answer 4

Muscarinic: mostly PANS/lytic
o SM, heart, exocrine glands
• In heart: Ach effects SA node: decrease cAMP, Ca into heart, contraction, HR
o Rest and digest

Nicotinic receptors
• Neuronal (Nn ) / muscular (Nm)
• Autonomic ganglia (neuronal)
• Skeletal muscle (muscular)

o AcH effects at NMJ: Ach hits nicotinic receptor -> creates action potential -> muscle contracts
-> Block nicotinic receptor = block contraction

Question 5

nicotine

Answer 5

Complex effects as a drug due to nonspecific activation of autonomic ganglia and skeletal muscle
o Peripheral SANS response typically dominates (increase HR, BP, sweating)
o Somatic: skeletal muscle relaxation
o Central: increase alertness in a drowsy subject and relaxation in tense subject
o Stimulates mesolimbic DA system (reward pathway)  can lead to dependence

Question 6

Alzheimer’s Disease:

Answer 6

Cholinergic neurons are predominantly lost–Drugs aim to increase Ach activity/concentration
o Primarily muscarinic receptors in CNS
o AD patients especially sensitive to anti-ACh drugs

AChI Place in Therapy for Alzheimer’s Disease (AD)
o Attempt to offset loss of presynaptic cholinergic function to slow decline of memory and enhance ability to perform activities of daily living (ADLs) - Drugs must cross BBB (lipophilic)

o Central drug effects&raquo_space; peripheral drug effects
o AD progression -> cholinergic neuronal loss -> diminished AChI efficacy
o AChI’s in AD are more selective for AChE in the brain (other AChI’s are less selective and also less able to cross the BBB)

Question 7

Myasthenia Gravis (MG)

Answer 7

o Autoimmune disease affecting skeletal muscle at neuromuscular junction (NMJ;
o muscular nicotinic receptors) -> diminished ACh activity
o Effect of AChI drug at the NMJ:
o Prolongs and intensifies the actions of physiologically-released ACh on muscular nicotinic receptors in NMJ

AChI’s in MG: Diagnose with short-acting AChI (edrophonium)
Treatment with neostigmine, pyridostigmine, or ambenonium

Question 8

“Cholinergic Crisis” vs. “Myasthenic Crisis”

Answer 8

o “Cholinergic Crisis”= too much ACh in NMJ (need less)-> Continuous stimulation = permanent depolarization
-> Concern for respiratory paralysis

o “Myasthenic Crisis”= not enough ACh in NMJ (need more) -> Similar to non-depolarizing neuromuscular blockade

Question 9

Organophosphates: Irreversible AChIs

Answer 9

o Pesticides: Malathion*, Parathion
o Nerve gas: Sarin
o Herbicides

o MOA: Covalent binding to enzyme active site leading to irreversible inhibition of AChE

o Leads to non-specific increase in ACh at peripheral and central muscarinic and nicotinic receptor site

Treatment of Organophosphate Toxicity
o Airway control, adequate oxygenation
o Decontamination, removal of all clothing
o Management of seizure: diazepam (benzodiazepine)

Question 10

Anticholinergics: Therapeutic Uses

Answer 10

o Nicotinic receptor antagonism
o Neuromuscular Blocker (NMB; muscular nicotinic)- Endotracheal intubation; surgery, Depolarizing (agonist) vs. Non-Depolarizing (antagonist)

o Muscarinic receptor antagonism
o Asthma/COPD
o Overactive bladder
o Parkinson’s disease

Question 11

antagonists at muscular nicotinic receptors

Answer 11

Antagonists at muscular nicotinic receptors–Competitively bind to nicotinic receptors on motor end plate (skeletal muscle) to antagonize ACh, resulting in blockade of neuromuscular transmission–Muscular inability to respond to a stimulus due to impaired ability to depolarize

o Results in skeletal muscle relaxation–Fine-movement muscles first (eyes, face, neck)

o Later -> limbs, chest, abdomen, diaphragm