9 - ANS Pharm and Cholinergic Agents

Muscarinic ACh System Includes

• Symp is T1-L3

  • Skin

• Parasymp is CNs and S2-S4

  • Stimulation with ACh causes rest and digest

Nicotinic ACh System Includes

• Somatic NS

  • Nicotinic receptor

    • ACh → skeletal muscle contraction

Steps for ACh Release to Cells

• Choline combines with Acetyl-CoA (via Cholineacetyltransferase) → ACh

• Action potential causes Ca2+ influx → ACh vesicles fuse and endocytose

• ACh binds receptors:

  • Nicotinic for skeletal muscle (let's Na+ inside)

  • Muscarinic

    • Gi (inhibitory)

      • Gi takes a GTP → GDP

      • Adenyl Cyclase is inhibited, so it can’t make ATP → cAMP → PKA (K+ leaves, hyperpol.)

    • Gq (stimulatory)

      • Gq takes GTP → GDP

      • Phospholipase C is stimulated to create PIP2 → (DAG → PKC) & (IP3 → Ca2+ depol.)

• ACh is taken up by Acetylcholinesterase (AChE) → Becomes Choline → Cycle Repeats

List Cholinergic Agonists (direct)

• Muscarinic agonists

  • Acetylcholine

  • Bethanechol

  • Cevimeline

  • Methacholine

  • Pilocarpine

• Nicotinic agonist

  • Varenicline

List Acetylcholinesterase Inhibitors (indirect)

Edrophonium

Neostigmine

Pyridostigmine

Physostigmine*

Donepezil*

*= tertiary amine (lipophilic, crosses BBB)

List Cholinergic Antagonists (direct)

(AKA anticholinergics)

(AKA muscarinic antagonists)

• Atropine

• Benztropine

• Darifenacin

• Diphenhydramine

• Glycopyrrolate**

• Ipratropium**

• Oxybutynin

• Scopolamine

• Tiotropium**

• Tropicamide

List Ganglion Blocker (Nicotinic Antagonist) (direct)

Mecamylamine

List Acetylcholinesterase (AChe) Regenerator (indirect)

Pralidoxime

Parasympathetic Pre/Postganglionic Transmitters and Receptors

Pre: ACh → Nn receptors (ganglia)

Post: ACh → M

Sympathetic Pre/Postganglionic Transmitters and Receptors

Pre:

• Ach → Nn receptors (ganglia)

Post:

• NE → Alpha or Beta receptors

• ACh → M (sweat on skin)

• DA → Dopamine D1 (renal vasodilation/perfusion)

List the Metabotropic Adrenergic (NE) Receptors

Alpha 1

Alpha 2

Beta 1

Beta 2

Alpha 1 Location, G-Protein, & Effects

“1 squeeze vessels and smooth muscle”

Blood vessels & Smooth muscles

Gq (↑ IP3 & DAG & Ca2+)

Contracts smooth muscles and vessels (increases BP)

Alpha 2 Location, G-Protein, & Effects

Presynaptic terminals

Gi (↓ cAMP & Ca2+)

Feedback inhibits NE release

Beta 1 Location, G-Protein, & Effects

“1 heart beats harder”

Gs (↑ cAMP & PKA & Ca2+)

↑ heart rate and contraction

Beta 2 Location, G-Protein, & Effects

Lungs (“2 lungs & smooth muscle relax”), Heart, Liver, Smooth muscle (uterus, bladder).

Gs (↑ cAMP & PKA)

Relaxes smooth muscle, Bronchodilation, Relax detrusor, Vasodilation, ↓ peristalsis

List the Metabotropic Muscarinic (ACh) Receptors

M2

M3

M2 Location, G-Protein, & Effects

Heart (“way 2 My heart”)

Gi (↓ Ca2+, hyperpolarizes the cell)

↓ HR and ACh release

M3 Location, G-Protein, & Effects

Everywhere else

Gq (↑IP3 (Ca2+), DAG, PKC)

Glands, GI, bronchioles, eyes, etc. (↑ contraction and secretions)

Ionotropic Nicotinic (ACh) Receptors

Nn for brain

Nm for NMJ (skeletal)

Myasthenia Gravis (MG)

Autoimmune disease, autoantibodies attack nicotinic receptors and block nicotinic binding sites

Causes weakness

Tx = meds that inhibit AChE (ACh build-up to kick out blockers)

Botulinum Toxin

Inhibits ACh release from terminal

Causes paralysis

Cholinesterase Inhibitor Toxicity (Cholinergic Crisis)

(causes, symptoms, tx)

Caused by:

• Neostigmine or Pyridostigmine

• Too much ACh because AChE is overly inhibited!

DUMBBELSS

• Digestion/Diarrhea

• Urination

• Miosis

• Bradycardia

• Bronchoconstriction

• Emesis

• Lacrimation

• Salivation

• Sweating

Tx:

• Atropine (muscarinic antagonist, prevents ACh overload)

• Pralidoxime (AChE regenerator, restores nicotinic function)

Anticholinergic Toxidrome (toxicity)

(causes, symptoms, tx)

Caused by:

• Too little ACh means no CNS stimulation, you can’t sweat (so your temp rises), you turn red, your mucous membranes can’t secrete anything

“Mad as a hatter

Red as a beet

Hot has a hare

Dry as a bone”

Tx:

• Cholinesterase inhibitors (physostigmine!)

Increased Intraocular Pressure (IOP)

Muscarinic antagonists (anticholinergics) can all cause THIS.

(dilate the pupil via relaxing iris sphincter)

This blocks the canal of Schlemm and causes increased intraocular pressure

Secretions

These function to decrease risk of infection

Halitosis

Bad breath, improves with salivation

Myasthenia Gravis (MG)

N receptors are blocked, need a bunch of Ach to knock it off via AChE inhibitors!

Edrophonium diagnoses it

Neostigmine treats it short term

Pyridostigmine treats it long term

NET vs AChE

• NE uses THIS reuptake

• ACh is broken down by THIS

Vasodilation

THIS involves sympathetic only, no parasymp.

Indirect Agent

“No vascular effect” implies THIS

Cycloplegia

No accommodation

Diarrhea

THIS is a result of increased bowel activity

Atropine

Belladonna plant has THIS

Pilocarpine and Physostigmine

2 things that can fix atropine toxicity are:

• Muscarinic agonist or Indirect Antagonist (that can cross the BBB)

  • THIS is agonist

  • THIS is indirect antagonist (uncharged so it can cross the BBB)

COPD

You need antimuscarinic drugs to treat THIS

Tropicamide

Antimusc. For eye only

Oxybutynin

Antimusc. For bladder

Muscarinic blockers

THESE reverse bradycardia (Bradycardia comes from too much ACh)

Postural Hypotension

THIS is due to the sympathetic blockade (not part of parasymp.)

Due to nicotinic