Part 1. Cholinergic Receptor Agonists

Question 1

What are the Mechanisms of Action of Cholinergic Agents?

Answer 1

Direct-Acting and Indirect-Acting

Question 2

What is the MOA of Direct-Acting Cholinergic Agonists?

Answer 2

They bind to and activate muscarinic and/or nicotinic receptors

Question 3

What is the MOA of Indirect-Acting Cholinergic Agonists?

Answer 3

They inhibit AChE (more ACh is available to receptors)

Question 4

Selectivity of Cholinergic Drugs:

Answer 4

Selectivity for receptor type: Either M or N

Selectivity for receptor subtypes: Prefers N receptors at neuromuscular junctions over N receptors in ganglion

Selectivity dependent on route of administration (PK Selectivity)

Question 5

Direct-acting cholinergic drugs are categorized based on their chemical structures. What two types are there?

Answer 5

Choline Esters and Alkaloids

Some are selective for M or N receptors

Question 6

What makes choline esters less susceptible to cholinesterase?

Answer 6

Methyl group at the beta carbon (methacholine), carbamic acids esters (carbachol), or both a methyl and carbamic acid (bethanechol)

Question 7

What is the preferred SAR for M agonist activity?

Answer 7

1) Nitrogen capable of bearing a positive charge
2) Size of alkyl groups on the nitrogen should not be larger than a methyl for max potency
3) Should have an O atom, preferable ester-like that can produce a hydrogen bond
4) Two carbon separation between the O and N atoms

Question 8

ADME of Choline Esters:

Answer 8

• Poorly absorbed
• Poorly distributed into the CNS
• All hydrolyzed in the GI tract
• Susceptibility to hydrolysis by AChE:
  ACh > methacholine > carbamic acid esters (carbachol > bethanechol)

Question 9

Acetylcholine

Answer 9

• Prototypical muscarinic (and nicotinic) agonist
• Poor therapeutic agent
• Lack of specificity (muscarinic vs nicotinic)
• Physicochemical properties related to its ester (=rapidly hydrolyzed) and quaternary ammonium group (=very poorly absorbed across lipid membranes)

Question 10

Methacholine Chloride (Provocholine)

Answer 10

• Selective muscarinic agonist
• Marketed as racemic mixture of S (+) and R (-)
enantiomers
• S (+) enantiomer 240 x more potent than R (-)
(R (-) weak inhibitor of AChE)
• Hydrolyzed by AChE at about 1⁄2 rate of ACh
• Used in diagnosis of asthma (methacholine challenge test)

Question 11

Carbachol Chloride (Carboptic, Isopto Carbachol)

Answer 11

• No muscarinic/nicotinic selectivity
• Carbamate ester, therefore more resistant to acid, base or
enzyme hydrolysis than ACh
• Weak inhibitor of AChE
• Variable absorption and nicotinic effects limit clinical use – glaucoma and induction of miosis (pupillary constriction) for ocular surgery
• Available as intraocular and ophthalmic solution

Question 12

Bethanechol Chloride (Urecholine, Duvoid)

Answer 12

• Carbamate analog of methacholine
• Selective for muscarinic receptors
• Postsurgical and postpartum urinary retention and abdominal distension
• Orally administered due to danger of cholinergic crisis if given by IV or IM injection

Question 13

ADME of Cholinergic Alkaloids:

Answer 13

• Well absorbed
• Nicotine sufficiently lipophilic to be absorbed across
the skin
• Muscarine is a charged quaternary amine - less GI absorption than the tertiary amines
• Lobeline is similar to nicotine
• Primarily all excreted by the kidneys (renal
elimination)

Question 14

Pilocarpine Hydrochloride (Carpine)

Answer 14

• Alkaloid from Pilcarpus jaborandi
• Marketed as tablets (Salagen), opthalmic solution, and gel
• Penetrates the eye – a miotic for open-angle glaucoma and to terminate acute angle closure attacks
• Treatment of xerostomia (dry mouth)
• A lactone subject to hydrolysis and epimerization to inactive stereoisomers of pilocarpine

Question 15

Cevimeline Hydrochloride (Evoxac)

Answer 15

• Non classical muscarinic agonist – quinuclidine
derivative
• Partial M1 agonist in CNS
• Affinity for M3 receptors in the lacrimal & salivary
glands
• Metabolized by CYP2D6, 3A3 & 3A4 to inactive metabolites
• Available as oral capsule for xerostomia due to Sjogren’s syndrome

Question 16

Nicotine & Varenicline (Chantix)

Answer 16

• Activity at the presynaptic a4b2 nicotinic receptor in CNS associated with pleasurable feelings of smoking due to receptor mediated DA release
• Nicotine patches, nasal spray, gum, inhaler are effective for smoking cessation in motivated patients
• Varenicline (Chantix) is a partial agonist of a4b2 nicotinic receptors with persistent (long t1/2) antagonist properties that prevent the stimulant effect of nicotine

Question 17

MOA of Cholinergic Receptor Stimulants:

Answer 17

1) ACh released from postganglionic parasympathetic nerves directly activates muscarinic receptors on effector organs
2) ACh released from parasympathetic nerves can interact with muscarinic receptors on other nerve terminals to inhibit release of their neurotransmitter

Question 18

All Cholinergic Agents at Muscarinic Receptors are what type of receptors?

Answer 18

GPCR

Question 19

MOA of Cholinergic Agents at Muscarinic Receptors:

Answer 19

• agonist binding (M1/M3/M5) activates the IP3-DAG cascade & increases intracellular cGMP
• DAG opens Ca++ channels
• IP3 releases sequestered Ca++ from the endoplasmic and
sarcoplasmic reticulum
• K+ flux increase across the cardiac cell membrane (M2)
• K+ flux decrease in ganglion and smooth muscle cells (M2)
• agonist binding inhibits (M2/M4) adenylyl cyclase in some tissues (e.g., heart, intestine) =  cAMP

Question 20

MOA of Cholinomimetics at Nicotinic Receptors:

Answer 20

• agonist binding to a nicotinic receptor –> conformational change in the protein –> opens ion channel –> Na+ & K+ diffuse down their concentration gradient
• prolonged occupancy of the receptor abolishes the response
  • postganglionic neuron stops firing
  • skeletal muscle relaxes
  • prevents the electrical recovery of the post-junctional membrane or “depolarizing blockade”

Question 21

Pharmacological Actions of ACh in the Cardiovascular System:

Answer 21

Primary effect of M agonists:

 - Increase PVR and change HR
 - Small ACh dose - decrease BP and increase HR
 - Large ACh dose - decrease BP and decrease HR
      - Decrease chronotropy and decrease ionotropy

Question 22

Direct Cardiac Actions of Muscarinic Agonists:

Answer 22

• Direct Increased K+ current in SA and AV nodes, Purkinje cells and cardiac muscle cells
• Decreased, slow inward Ca++ currents
• Reduction in hyperpolarization-activated current
determining diastolic depolarization

Question 23

What do all M2 cardiac receptor agonists do?

Answer 23

Slow SA and AV rates and contractility

Question 24

Vascular Effects of Muscarinic Agonists:

Answer 24

• ACh from postganglionic parasympathetic nerves relaxes vascular smooth muscle via NO/cGMP
• Skeletal muscle vasculature innervated by sympathetic cholinergic nerves
• Skeletal muscle vasculature responds to exogenous choline esters (M3 receptors)

Question 25

Muscarinic Effects of ACh in the Eye:

Answer 25

* Direct instillation to conjunctival sac of the eye results in miosis * Contraction of smooth muscle sphincter of the iris * Contraction of the ciliary muscle (accommodation)

Question 26

What are the pharmacological actions of ACh in other | systems?

Answer 26

Resembles actions produced by postganglionic parasympathetic stimulation

Question 27

Moderate doses of ACh in lungs:

Answer 27

Increase bronchial constriction & secretions

Question 28

Moderate doses of ACh in glands:

Answer 28

Stimulates lacrimal, salivary, and sweat glands

Question 29

Moderate doses of ACh in urinary bladder:

Answer 29

Contraction and decreased bladder capacity (promotes voiding)

Question 30

Higher doses of ACh stimulates the GI tract by:

Answer 30

Increasing smooth muscle resting tone, force of contraction, & GI secretion (in some cases with nausea and vomiting)

Question 31

Pharmacological Actions of ACh on CNS:

Answer 31

• muscarinic and nicotinic receptors in CNS • nicotine and lobeline have important effects in brain stem and cortex - Presynaptic nicotinic receptors mediate ACh and Nicotine neurotransmitter release (glutamate, GABA, serotonin, NE, dopamine) - ACh regulates NE release via an α3β4-type nicotinic receptor (hippocampus) / inhibits ACh release (hippocampus & cortex)

Question 32

Pharmacological Actions of ACh on the Peripheral Nervous System:

Answer 32

- Nicotinic agonists activate nicotinic receptors on postganglionic neurons in autonomic ganglia - Action on both sympathetic & parasympathetic ganglia - Effect resembles firing of both sympathetic and parasympathetic systems • CV – sympathetic effects dominate – hypertension & sympathetic tachycardia (possibly alternating with bradycardia – parasympathetic) • GI – parasympathetic effects dominate (nausea, vomiting, diarrhea, urinary voiding)

Question 33

What happens to prolonged activation of N receptors by N agonists in the autonomic ganglia?

Answer 33

Prolonged activation leads to depolarizing blockade of the ganglia

Question 34

Pharmacological Actions of ACh on Neuromuscular Junction:

Answer 34

- Nicotinic receptors on skeletal muscle respond to ACh and nicotine - Exposure to a nicotinic agonist causes immediate depolarization of the neuromuscular end plate (Na+ and K+ permeability) • fasciculation of independent motor units or • synchronized contraction of the entire muscle

Question 35

Nicotinic Actions of ACh:

Answer 35

- Exogenously administered ACh does not readily distribute to skeletal muscle and autonomic ganglia - Blockade of muscarinic receptors (atropine) permits nicotinic effects to be seen - Stimulation of nicotinic receptors in: - parasympathetic ganglia results in no change in effector organ - sympathetic ganglia changes effector organ activity - the adrenal medulla results in release of catecholamines to the circulation

Question 36

Net result of nicotinic stimulation in presence of muscarinic blockade is:

Answer 36

Massive sympathetic activity

Question 37

Nicotinic actions of ACh on skeletal muscle results in:

Answer 37

Nicotinic stimulation of skeletal muscle