RCS 04 - Cholinergic Agonists & Antagonists 1

Question 1

Answer 1

A

Question 2

List and describe the types of cholinergic agonists

Answer 2

• Direct Acting Agents - bind to and activate muscarinic or nicotinic receptors
• Indirect Acting Agents - inhibit Ach-esterases

Question 3

Are the therapeutically useful direct acting angents usually activating muscarinic or nicotinic receptors?

Answer 3

Muscarinic

Question 4

List the direct affects of Ach on the CVS we need to know. Are these effects always seen?

Answer 4

M2 effect - decrease in HR, force of heart contraction, and in rate of conduction in SA and AV nodes

M3 effect - vasodilation

These effects are not always seen because homeostatic reflexes may dampen or reverse them.

Question 5

List the direct effects of Ach on non-CVS tissues that we need to know.

Answer 5

• Sphincter Pupillae Constriction - Miosis
• Ciliary Muscle Constriction - lens accomodation for near vision
• Salivary/Sweat/Lacrimal Glands - increase in secretion
• Bronchi - constriction and increase in secretion
• GIT - increased tone, peristaltic activity, secretions, and relaxation of sphincters
• Contraction of detrusor muscles and relaxation of the urethral sphincter to facilitate urination

Question 6

Important note about low and high doses of ACh.

Answer 6

Both low and high doses of Ach will cause a drop in MAP and PVR. However, a low dose of Ach will cause an increased HR while a high dose will cause a decreased HR.

Question 7

How can you give ACh so that only the nicotinic effects are seen? What are these nicotinic effects and what is the mechanism of activation?

Answer 7

You can block the muscarinic effects by administering a muscarinic antagonist, like atropine, before adminstering the ACh.

Primary effects seen are both an increase in BP and vasoconstriction

These effects are due to stimulation of the sympathetic ganglia and release of E from the adrenal medulla

Question 8

List the subtypes of direct acting cholinergic agonists

Answer 8

Choline Esters

Alkaloids

Question 9

List the primary characteristic of choline esters that we need to know.

Answer 9

• They’re quaternary ammoniums, which means they’re charged, making them poorly absorbed and poorly distributed into the CNS

Question 10

List the choline esters we need to know and comment on how resistant to cholinesterases they are.

Answer 10

• ACh - very rapidly hydrolyzed
• Methacholine, carbachol, and bethanechol - more resistant to hydrolysis

Question 11

What are the primary uses of ACh

Answer 11

To obtain rapid miosis after delivery of the lens in cataract surgery and other procedures where rapid miosis is required

No systemic therapeutic applications due to its multiplicity of actions and rapid hydrolysis

Question 12

What types of receptors does Bathanechol activate and what are its primary uses?

Answer 12

Muscarinic agonist

Primarily used to treat postoperative/postpartum urinary retention or any other type of urinary bladder atony

Question 13

What types of receptors does Carbachol activate and what are its primary uses?

Answer 13

Activates both muscarinic and nicotinic receptors

Used to elicit miosis during surgery and reduce intraocular pressure after cataract surgery

Question 14

What types of receptors does Methacholine activate and what are its primary uses?

Answer 14

Muscarinic agonist

Primarily used to diagnose bronchial airway hyperreactivity (asthma) in subjects who do not have clinically apparent asthma (their FEV fraction appears OK)

Question 15

List the alkaloids we need to know

Answer 15

Pilocarpine

Nicotine

Question 16

Describe what type of molecule pilocarpine is and what that means about its pharmacokinetics. What type of agonist is pilocarpine? What are its typical uses? Is it readily hydrolyzed by ACh-esterases?

Answer 16

• Pilocarpine is a tertiary amine which means it is uncharged and regularly diffuses into the tissues
• Partial agonist of muscarinic receptors
• Uses:
  
  • Second line agent for open angle glaucoma
  • Management of acute angle-closure glaucoma
  • Treatment of dry mouth caused by radiotherapy or Sjogren’s syndrome
• Resistant to hydrolysis by ACh-esterases

Question 17

What are the adverse effects of muscarinic agonists?

Answer 17

• Glandular Effects - sweating and salivation
• CVS Effects - flushing and low BP
• GIT Effects - nausea, abdominal pain, diarrhea, bronchospasm

Question 18

Describe the structure, mechanism of action of nicotine, and general effects caused by nicotine.

Answer 18

• Tertiary amine (readily distributed into tissues)
• Selective nicotine receptor agonist
• At low doses, nicotine depolarizes both PSNS and SNS ganglia. At high doses, it causes a ganglionic and neuromuscular blockade (paralysis)

Question 19

Describe the actions of nicotine on the CVS, GI & Urinary Tracts, and Secretions.

Answer 19

• CVS - while the CVS is primarily controlled by the PSNS, nicotine will cause E & NE release from nerve terminals and the adrenal medulla, leading to a sympathomimetic effect. Increase in HR and BP.
• GI and Urinary Tracts - mainly parasympathomimetic effects. Nausea, vomiting, diarrhea, voiding of urine.
• Secretions - inscreased salivary and bronchial secretions

Question 20

What are the symptoms of acute severe nicotine poisoning?

Answer 20

Nausea, Salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental confusion, weakness. BP drop, weak pulse.

Death may occur from paralysis of respiratory muscles and/or central respiratory failure (ganglionic block of respiratory centers).

Question 21

What are the therapeutic uses of nicotine?

Answer 21

Just smoking cessation therapy

Question 22

List the indirect acting cholinergic agonists we need to know.

Answer 22

• Edrophonium
• Carbamates
  
  • Physostigmine
  • Neostigmine
  • Pyridostigmine
• Organophosphates
  
  • Echothiophate
  • Parathion
  • Malathion
  • Sarin gas

Question 23

Describe the mechanisms of action of edrophonium, carbamates, and organophosphates. Be sure to highlight important differences and comment on the length of time these drugs are effective.

Answer 23

• Edrophonium binds reversibly to the active of site of ACh-esterases. Relatively short-lived effect
• Carbamates form a covalent bond with the ACh-esterases. Longer lived effect
• Organophosphates form a covalent bond with the ACh-esterases and phosphorylates them. This phosphorylation causes the ACh-esterase to undergo a process called ageing, which further stabilizes the covalent bond. Very long-lived effects

Question 24

Describe the effects of ACh-esterase inhibitors on the CNS.

Answer 24

• In low doses, liposouble ACh-esterase inhibitors cause CNS activation
• In high doses, they cause convulsions which can possibly be followed up by coma and/or respiratory arrest

Question 25

Describe the effects of ACh-esterase inhibitors on the eye, respiratory tract, GIT, and Urinary tract.

Answer 25

Similar to the effects of direct acting cholinergic agonists.

Question 26

Describe the effects of ACh-esterase inhibitors on the CVS.

Answer 26

• They activate both SNS and PSNS ganglia supplying the heart, however, PSNS effects predominate (M2 effect) causing negative chronotropic (decreased HR), dromotropic (decrease in AV node conduction), and inotropic (decreased force of contraction) effects.
• At low doses, there is no effect on the vasculature because these receptors are not innervated. At moderate doses they cause an increase in systemic vascular resistance and BP by activating sympathetic ganglia and central sympathetic centers.

Question 27

Descibe the effects of ACh-esterase inhibitors on the NMJ? What are their particular uses in this area?

Answer 27

• Cholinesterase inhibitors will increase the strength of contraction
• They are in treating myasthenia gravis or reversing the action of nondepolarizing NMJ blockers

Question 28

Describe the structure, distribution profile, and uses of Edrophonium.

Answer 28

• Quaternary ammonium
• Does not enter CNS
• Used in diagnosis of myasthenia gravis and to reduce the neuromuscular block produced by non-depolarizing muscular blockers

Question 29

Describe the structure, distribution profile, and uses of Physostigmine.

Answer 29

• Tertiary amine
• Can enter CNS
• Used in the treatment of anticholinergic drug OD (atropine)

Question 30

Describe the structure, distribution profile, and uses of Neostigmine

Answer 30

• Quaternary ammonium
• Does not enter CNS
• Used to treat:
  
  • postoperative urinary retention
  • reversal of effects of non-depolarizing muscle blockers after surgery
  • Myasthenia gravis

Question 31

Describe the structure, distribution profile, and uses of Pyridostigmine.

Answer 31

• Quaternary ammonium
• Does not enter CNS
• Used to treat myasthenia gravis

Question 32

What are the uses for the organophosphates?

Answer 32

• Echothiophate - very rarely used for glaucoma
• Malathion & Parathion are insecticides
• Sarin is a weapon

Question 33

What drugs are used to prolong the onset of Alzheimer symptoms?

Answer 33

Centrally acting AChE inhibitors:

• Donepezil
• Rivastigmine
• Galantamine

Question 34

What drugs are given to treat AChE inhibitor ODs? What are these drugs mechanism of action?

Answer 34

Pralidoxime can be used as a AChE regenerator but it must be given before any AChE ageing occurs.

Pralidoxime acts by splitting the phosphorous-enzyme bond

Question 35

Answer 35

D