Ach Agonists

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What is one of the primary therapeutic uses of pilocarpine?

Prevention of diarrhea

Reduction of eyelid spasms

Inhibition of muscarinic receptors

Treatment of xerostoma (correct)

Which of the following statements about pilocarpine is true?

It is directly acting and derived from natural sources. (correct)

It only acts on nicotinic receptors.

It is rapidly metabolized by acetylcholinesterase.

It causes mydriasis in the eye.

What occurs as a result of muscarinic toxicity from pilocarpine overdose?

Increased heart rate

Nausea and salivation (correct)

Severe agitation and hyperactivity

Dilation of bronchial passages

Which enzyme is responsible for terminating the actions of acetylcholine?

Acetylcholinesterase Signup and view all the answers

Which condition is pilocarpine NOT used to treat?

Dysphagia Signup and view all the answers

What effect does the entry of pilocarpine into the CNS most likely cause?

Marked salivation and sweating Signup and view all the answers

What is a common side effect of cholinergic toxicity?

Fasciculations and paralysis Signup and view all the answers

In which of the following is butyrylcholinesterase found?

Liver and serum Signup and view all the answers

What clinical effect does methacholine have on the heart?

Decreases conduction velocity Signup and view all the answers

Which direct acting agonist is primarily used for treating urinary retention?

Bethanechol Signup and view all the answers

Which second messenger is released from intracellular stores due to G Protein activation?

Inositol-1,4,5-trisphosphate (IP3) Signup and view all the answers

What mechanism of action does carbachol utilize for treating glaucoma?

Activates the pupillary sphincter Signup and view all the answers

In terms of the gastrointestinal system, what outcome is expected with muscarinic agonist administration?

Increased motility and secretion Signup and view all the answers

Which of the following conditions is the pharmacodynamics of nicotine related to?

Smoking cessation Signup and view all the answers

What is the primary action of atropine on muscarinic receptors?

Inhibition of secretions Signup and view all the answers

Which drug listed is a direct acting agonist for glaucoma treatment and is a synthetic derivative?

Carbachol Signup and view all the answers

What is the duration of effect for Carbamate Ester Drugs?

30 minutes to 6 hours Signup and view all the answers

Which of the following accurately describes Quaternary Alcohol Drugs?

They bind with weak hydrogen bonds and last for 2 - 10 minutes. Signup and view all the answers

What is a significant characteristic of Organophosphates compared to Carbamates?

They are lipid soluble and well absorbed into the CNS. Signup and view all the answers

What action occurs in the heart when using cholinolytics?

Increase heart rate Signup and view all the answers

Which statement about indirect acting cholinomimetics is correct?

They amplify the actions of endogenous Ach. Signup and view all the answers

What is the primary effect of cholinomimetics on the gastrointestinal (GI) system?

Increase motility Signup and view all the answers

Which receptors are found at all autonomic ganglia?

Nicotinic receptors Signup and view all the answers

In the context of cholinolytics, what effect occurs in the respiratory system?

Bronchodilation Signup and view all the answers

What was one of the main uses of TOCP in industrial applications?

As a plasticizer in synthetic materials Signup and view all the answers

Which of the following describes an effect of TOCP exposure?

Acute cholinergic effects Signup and view all the answers

Which symptoms are associated with TOCP poisoning?

Irreversible muscle weakness and paralysis Signup and view all the answers

What is currently understood about the mechanism of action of TOCP?

The mechanisms are not well understood and may involve multiple enzymes Signup and view all the answers

What is the primary action of neostigmine in clinical settings?

To increase bladder tone and promote urine flow Signup and view all the answers

Which drug is notably used in the treatment of Alzheimer’s disease as an AchE inhibitor?

Donepezil Signup and view all the answers

What type of disease is Myasthenia gravis primarily categorized as?

An autoimmune receptor disease Signup and view all the answers

What was the primary reason for the initial use of physostigmine in treating Myasthenia gravis?

To increase the amount of acetylcholine available at the junction Signup and view all the answers

What is the mechanism of action of tetanospasmin that results in excess acetylcholine release?

Blockage of GABAergic neurons Signup and view all the answers

Which of the following is NOT a clinical application of cholinesterase inhibitors?

Treatment of hypertension Signup and view all the answers

What adverse effects can result from excess acetylcholine due to AchE inhibitors?

Nausea, diarrhea, and vomiting Signup and view all the answers

What is the primary treatment for myasthenia gravis to enhance neuromuscular transmission?

Physostigmine to inhibit AchE Signup and view all the answers

Which of the following symptoms is NOT typically associated with overdose of acetylcholinesterase (AchE) inhibitors?

Dry mouth Signup and view all the answers

What factor increases the toxicity of organophosphate pesticides when exposed?

“Aging” of the AchE-Agent complex Signup and view all the answers

What was the primary consequence of using TOCP in Jamaica Ginger extracts in 1930?

Severe paralysis in thousands Signup and view all the answers

Which of the following clinical manifestations is part of the DUMBBELSS acronym linked to AchE toxicity?

Lacrimation Signup and view all the answers

What is the main therapeutic approach for managing toxicity from AchE inhibitors?

Supportive care and atropine administration Signup and view all the answers

Which class of substances is primarily responsible for the majority of cholinesterase inhibition in the environment?

Organophosphates Signup and view all the answers

Which of the following is catabolic?

Sympathetic Nervous System (SNS) Signup and view all the answers

Which of the following is anabolic, craniosacral and short postganglionic?

Parasympathetic Nervous System (PNS) Signup and view all the answers

What does anabolic mean?

Conserve energy, also called the craniosacral system Signup and view all the answers

What do all parasympathetic postganglionic fibers release?

Acetylcholine (Ach) Signup and view all the answers

What receptors does Acetylcholine bind to?

Both muscarinic and nicotinic receptors Signup and view all the answers

What do most sympathetic postganglionic fibers release?

Norepinephrine (NE) Signup and view all the answers

Which receptors does norepinephrine bind to?

Alpha and beta receptors Signup and view all the answers

What do sweat glands release?

Acetylcholine Signup and view all the answers

What is acetylcholine synthesized from?

acetyl coenzyme A (acetyl CoA) Signup and view all the answers

What is the sequence of norepinephrine and epinephrine synthesis?

tyrosine --> dopa --> dopamine --> NE --> EP Signup and view all the answers

Which enzyme removes acetylcholine?

Acetylcholinesterase (AchE) Signup and view all the answers

Which of the following does not remove Norepinephrine (NE) and Epinephrine (EP)?

Acetylcholinesterase Signup and view all the answers

Which forms can monoamine oxidase (MAO) exist in?

MAO A Signup and view all the answers

What are two ways in which a drug may work?

Raise a neurotransmitter (NT) level Signup and view all the answers

Which neurotransmitter can be blocked with the use of an agonist at an alpha-2 adrenergic presynaptic receptor?

Norepinephrine (NE) Signup and view all the answers

What do cholinoreceptors affect?

Ach neuronal activity and all aspects of Ach Signup and view all the answers

What are direct acting cholinoreceptor stimulants?

Drugs that mimic Ach, act like Ach, and bind to nicotinic and muscarinic Ach receptors Signup and view all the answers

Where are nicotinic receptors located?

motor end plate on muscles Signup and view all the answers

Where are muscarinic receptors primarily located?

Glands Signup and view all the answers

What does acetylcholine do?

Muscles to fire Signup and view all the answers

Match each to its group

Choline Ester Cholinoceptor Drugs = acetylcholine Cholinoceptor Alkaloid Drugs: = muscarine Choline Ester Cholinoceptor Drugs = carbachol Cholinoceptor Alkaloid Drugs: = pilocarpine Signup and view all the answers

Match each to its description

pilocarpine = when applied to the skin will cause sweating, used to collect sweat for lab and chemical analysis (screen for cystic fibrosis acetylcholine = neurotransmitter carbachol = opical ophthalmic used only to treat glaucoma muscarine = poison found in many (not all) mushrooms Signup and view all the answers

Choline Ester Cholinoceptor Drugs are:

Hydrophilic and do not penetrate into the CNS very well. Signup and view all the answers

What do Direct Acting Cholinoceptor Stimulants (Muscarinic Agonists) do to the eye?

miosis from smooth muscle contraction Signup and view all the answers

What do cholinoceptor stimulants (muscarinic agonists) do to the cardiovascular system?

Decrease heart rate, decrease in contractile strength Signup and view all the answers

What do cholinoceptor stimulants (muscarinic agonists) do to the lungs?

Bronchoconstriction Signup and view all the answers

What do cholinoceptor stimulants (muscarinic agonists) do to the GI tract?

All of the above Signup and view all the answers

What do cholinoceptor stimulants (muscarinic agonists) do to the genitourinary tract?

Increase urination (contract detrusor muscle and relax trigone sphincter muscles) Signup and view all the answers

What do Direct Acting Cholinoceptor Stimulants (Muscarinic Agonists) do to the CNS?

Stimulate and inhibit a wide range of different neurotransmitters Signup and view all the answers

What effect do Direct Acting Cholinoceptor Stimulants (Muscarinic Agonists) have on glands?

secretion of sweat, salivary, lacrimal and nasopharyngeal glands Signup and view all the answers

What does the acronym DUMBBELSS stand for?

D= diarrhea U= urination M= miosis B= bronchoconstriction in lungs B= Bradycardia in heart E= excitation in CNS (mental confusion) L= lacrimation S= sweating S= salivation Signup and view all the answers

Match each indirect acting cholinomimetic drug to its class

<h1>Simple alcohol with quaternary ammonium group = edrophonium Carbamic acid esters of alcohol with quarternary or tertiary ammonium groups = neostigmine; physostigmine; pyridostigmine Organophosphates = sarin; malathion; echothiophate</h1> Signup and view all the answers

What are Indirect Acting Cholinomimetics?

Drugs that increase Ach by inhibiting acetylcholinesterase (AchE) Signup and view all the answers

Match each drug class to its MOA

<h1>edrophonium (Simple alcohol with quaternary ammonium group) = non-covalent binding to AchE, short lived binding, short duration of action Carbamic acid esters of alcohol with quarternary or tertiary ammonium groups (neostigmine; physostigmine; pyridostigmine) = 30 min to 6-hour duration of action organophosphates (sarin; malathion; echothiophate) = long duration of action, hundreds of hours, very lethal. These are the poison gases used in war and the agents used to kill plant eating bugs on the farm.</h1> Signup and view all the answers

What effect do Indirect Inhibitors have on the CNS?

Convulsions and death (dose dependent) Signup and view all the answers

What effects do indirect inhibitors have on the cardiovascular system? (Select all that apply)

Cardiac output falls Signup and view all the answers

What effects do indirect inhibitors have on the neuromuscular junction?

Neuromuscular blockade (higher doses) Signup and view all the answers

Match each drug to its effect on each system

<h1>treat intraocular high pressure in glaucoma = Direct agonist: pilocarpine, methacholine; Indirect agonists: physostigmine treat urinary retention = bethanechol treat myasthenia gravis/ diagnose it = edrophonium</h1> Signup and view all the answers

What is atropine?

A competitive inhibitor of Acetylcholine at muscarinic receptors Signup and view all the answers

What is used to treat atropine overdose?

Physostigmine Signup and view all the answers

Which of the following has the following description: AchE inhibitor that increases Ach levels in the CNS and slows down the progression of Alzheimer’s Disease?

donepezil Signup and view all the answers

Which of the following cholinomimetics are poorly absorbed and have a short half-life due to acetylcholinesterase (AchE)?

Choline Esters Signup and view all the answers

Which of the following cholinomimetics are well absorbed (some even into the CNS)?

Alkaloids Signup and view all the answers

Which Ach receptor is a G-protein coupled serpentine receptor?

Muscarinic Receptors Signup and view all the answers

Which Ach receptor is a ligand gates ion channel receptor?

Nicotinic Receptors Signup and view all the answers

Study Notes

Cholinomimetics

Cholinergic agonists mimic acetylcholine's actions, also known as cholinergics, and acetylcholine agonists, cholinoceptor-activating drugs, and cholinoceptor stimulants

Case Study

A 43-year-old male farm worker experienced unsteady gait, difficulty speaking and swallowing, blurred vision, tearing eyes, difficulty breathing, and tightness in the chest.
The fields were sprayed with a chemical that smelled like sulfur.
How to treat?

Case Report

Symptoms are typical of an acetylcholinesterase (AChE) inhibitor.
Decontaminate the patient (and yourself), remove clothing, and wash exposed areas of the skin.
Ventilate with oxygen (O₂).
Block excess ACh at muscarinic receptors with atropine intravenously (iv).
Block excess ACh at nicotinic receptors with 2-PAM (restore/reactivate inhibited AChE).

Drugs

carbachol
donepezil
pilocarpine
neostigmine
muscarine
physostigmine
nicotine
methacholine
rivastigmine
bethanechol
edrophonium
carbamate insecticides
organophosphate insecticides
nerve gas (e.g., suman, sarin)

Acetylcholine (ACh)

Drugs that mimic ACh. Also known as cholinergic agonists (cholinergics), acetylcholinesterase (AChE) agonists, cholinoceptor-activating drugs, or cholinoceptor stimulants

Direct Acting

Substitute for ACh and enhance the effects of ACh

Indirect Acting

Increase ACh levels by inhibiting the enzyme (AChE) that removes ACh

Part 1. Cholinomimetics: Direct Acting

Synthetics (Choline Esters):
- methacholine
- bethanechol
- carbachol
Alkaloids from Plants:
- pilocarpine
- muscarine
- nicotine

Cholinomimetics: Choline Esters

Poorly absorbed through oral routes (PO), do not enter the central nervous system (CNS).
Short half-life due to AChE (seconds to minutes).
Intramuscular (IM) injections produce only local effects.

Cholinomimetics: Alkaloids

Well absorbed, some even into the CNS.

ACh Receptors

Muscarinic receptors (G-protein coupled):
- Activation leads to inhibition or excitation
Nicotinic receptors (ligand-gated ion channels):
- Activation leads to excitation.

Cholinergic Receptors

Nicotinic
- Acetylcholine
- Nicotine
Muscarinic
- Acetylcholine
- Muscarine

Pharmacodynamics

Choline Ester Muscarinic Nicotinic
- ACh +++ +++
- methacholine ++++ none
- carbachol ++ +++
- bethanechol ++ none

Cholinomimetics (General)

Mimic acetylcholine (ACh) in actions.
Bind to muscarinic receptors (G-protein coupled) and/or nicotinic receptors (ion channel).
Key Table 7-1 (receptor subtypes and tissue locations) pg 106.

Cholinomimetics, Direct Acting

Drugs that stimulate receptors directly (agonists)
Choline Esters:
- acetylcholine (ophthalmic) (Miochol-E®)
- methacholine (Provocholine®)
- carbachol (ophthalmic) (Carboptic®)
- bethanechol (Urecholine®)
Naturally occurring agents (Alkaloids):
- muscarine (experimental usage)
- nicotine
- pilocarpine (ophthalmic) (Isopto Carpine®)

General Actions of Cholinomimetics (Typical side effects due to cholinergic overactivity)

Diarrhea
Diaphoresis (sweating)
Miosis (pupil constriction)
Nausea
Urinary urgency

Direct Acting (At Nicotinic Receptors)

(1) Ion channel opens and sodium flows into the cell.
(2) Nerve cell depolarizes and fires.
(3) Prolonged activation of the nicotinic receptor leads to termination of response and paralysis.

Chapter 7: Cholinoceptor-activating & Cholinesterase-inhibiting Drugs (Table 7-1)

Receptor Type, Other Names, Location, Structural Features, Postreceptor Mechanism.
- M1, M2, M3, M4, M5, NM, etc

Cholinergic Toxicity (pilocarpine overdose)

Nausea, vomiting, diarrhea, salivation, and bronchial constriction.
Effects reversed by atropine.
Some poisonous mushrooms contain muscarinic alkaloids.

Nicotine Toxicity

Central Nervous System (CNS) stimulation, including convulsions.
Peripheral Nervous System (PNS) neuromuscular block, leading to fasciculations and paralysis.

Part 2. AChE (Target of Indirect Acting Drugs)

ACh is broken down to choline + acetic acid.

Acetylcholine Neuron (Mechanism)

Acetyl-CoA and CoA.
Synaptic vesicle.
Acetylcholinesterase.
ACh receptor.
Presynaptic neuron Postsynaptic Neuron
synaptic cleft.

Cholinesterase Nomenclature

Acetylcholinesterase (AChE): True cholinesterase, Choline esterase I. Found in brain (gray matter), nerve terminals, and red blood cells. Function is to terminate ACh actions.
Butyrylcholinesterase (pseudocholinesterase): Choline esterase II. Found in the brain (white matter), liver, and serum. Function is unknown.

AChE Inhibitors (Indirect Acting, Reversible)

donepezil
neostigmine
physostigmine
rivastigmine
edrophonium

AChE Inhibitors (Indirect Acting, Slowly to Non-reversible)

carbamate insecticides
organophosphate insecticide (> 50,000 different ones)
nerve gases (e.g., suman, sarin)

AChE Forms and Differences

Both forms are inhibited by organophosphates and physostigmine
Both enzymes exist in multiple molecular forms (isozymes)
Many genetic allelic forms of the enzymes exist.
Pseudocholinesterase (serum AChE) levels are a useful liver function test.

Indirect Acting Cholinomimetics

Drugs bind to and inhibit AChE
- Quaternary Alcohols: edrophonium
- Carbamate Esters: neostigmine, physostigmine.
- Carbamate Insecticides: carbaryl (Sevin®), propoxur (Baygon®), aldicarb (Temik®)
- Organophosphates: parathion, malathion
- Nerve Gases: soman, sarin

Toxicity and ADRs of AChE Inhibitors

Accidental exposure to pesticides (e.g., parathion)
The degree of toxicity is related to the amount of time the agent remained bound to AChE.
"Aging" of the AChE-agent complex

Indirect Acting Actions

Actions similar to direct-acting cholinergic agents—increasing ACh levels.
Major sites of pharmacological action: cardiovascular, gastrointestinal (GI), eye, and skeletal muscles.

Indirect Acting Clinical Actions

Clinical effects amplify the actions of endogenous ACh.
Concentration, half-life, and actions of ACh at synapses increase.
Actions occur at nicotinic and muscarinic receptors

Indirect-Acting Clinical Uses

In diseases where increased ACh activity is beneficial:
- Urinary retention
- Myasthenia Gravis
- Glaucoma

Indirect Acting Clinical Uses (Eye, GI, and CNS)

EYE: glaucoma (increased intraocular pressure)
GI: atony or paralysis of the bowel without obstruction, or urinary retention (post-operative).
CNS: Alzheimer's disease

Alzheimer's Disease

Donepezil (Aricept®) approved by the FDA
AChE inhibitor that increases CNS ACh levels
ADRS from excess ACh: nausea, diarrhea, vomiting

Myasthenia Gravis

Autoimmune disease of the neuromuscular junction.
Patient antibodies bind to and reduce the number of nicotinic receptors.
IgG anti-receptor antibodies
AChE inhibitor drugs improve patient response by increasing the amount of ACh per reduced receptor number.

Mary B. Walker (1888-1974)

First to describe the use of physostigamine to treat Myasthenia gravis in 1934.

The Rationale for the Use of Physostigmine

Tetanus, caused by Clostridium tetani, secretes tetanus toxin (TT), causing muscular rigidity, spasms, and respiratory failure.
The mechanism involves blocking inhibitory neurons in the CNS, causing excess acetylcholine (ACh) outflow.
Tetanus is sometimes treated with curare due to its binding to nicotinic receptors, preventing ACh stimulation.
Myasthenia gravis, a curare-like paralysis, is treated with physostigmine to inhibit AChE and increase ACh at motor endplates.

Toxicity and ADRs

Accidental exposure to pesticides (parathion)
Degree of toxicity is related to how long the agent remains bound to AChE.
"Aging" of the AChE-agent complex makes reversal more difficult.

Indirect Acting (Toxic actions)

Toxic actions similar to direct-acting cholinergic agents—increasing ACh levels.
Major sources of cholinesterase inhibitors: Pesticides (~100 organophosphates and 20 carbamates in the US).
Toxicity similar to muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, diarrhea.
Treatment is supportive, including atropine.

Toxicity of AChE Agents (DUMBBELSS)

Diarrhea
Urination
Miosis (constricted pupils)
Bronchoconstriction
Bradycardia (<60 beats/min)
Excitation (CNS and skeletal muscles)
Lacrimation (tears)
Salivation
Sweating

Jamaica Ginger

Ethanol extract of Jamaica Ginger Root
Worldwide tonic in the 1920s.
Used to improve digestion and treat colds.

Jamaica Ginger (Prohibition in US)

Prohibition in 1920 changed laws on ethanol content in extracts.
Ethanol content reduced.
Molasses too expensive.

Tri Ortho Cresyl Phosphate (TOCP)

Clear liquid dissolves fat-soluble compounds.
Industrial uses include plasticizers, maintaining the brittleness of synthetic materials, and as an additive in cooling lubricants.

TOCP and Acute Cholinergic Effects

TOCP inhibits AChE and another esterase enzyme in the CNS and PNS.
Agent induces acute cholinergic effects, including delayed PNS neurotoxicity.
It causes irreversible muscle weakness, leg weakness, and paralysis.
Mechanism of action is not well understood and may involve AChE and/or other neuroesterases.

Ginger Jake Paralysis

Over 20,000 cases in the Eastern and Southern US in the early 1930s due to TOCP-contaminated Jamaican ginger.
10,000 cases of paralysis in Morocco in 1959 due to contaminated cooking oil.

TOCP Historical Context

Quotation from The Grapes of Wrath.
References to popular music of the 1930s.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.