Unit 2.2. Cholinergic Agonists

Acetyl-CoA

ACETYLCHOLINE LIFESPAN:

1. ___________ comes from the Kreb’s Cycle

2. ____________________ enters the ganglion to produce Acetylcholine

3. Acetylcholine is put inside a __________ to protect it from degradation

4. An increase in ______ allows Acetylcholine to be released, moving it to the end of the ganglion.

5. Acetylcholine binds to ____________________ to produce a parasympathetic response

6. Acetylcholine can be degraded/metabolized into a._______ to be recycled and b.______ to be excreted.

1 = ?

Acetyl-CoA and Choline

ACETYLCHOLINE LIFESPAN:

1. ___________ comes from the Kreb’s Cycle

2. ____________________ enters the ganglion to produce Acetylcholine

3. Acetylcholine is put inside a __________ to protect it from degradation

4. An increase in ______ allows Acetylcholine to be released, moving it to the end of the ganglion.

5. Acetylcholine binds to ____________________ to produce a parasympathetic response

6. Acetylcholine can be degraded/metabolized into a._______ to be recycled and b.______ to be excreted.

2 = ?

vesicle

ACETYLCHOLINE LIFESPAN:

1. ___________ comes from the Kreb’s Cycle

2. ____________________ enters the ganglion to produce Acetylcholine

3. Acetylcholine is put inside a __________ to protect it from degradation

4. An increase in ______ allows Acetylcholine to be released, moving it to the end of the ganglion.

5. Acetylcholine binds to ____________________ to produce a parasympathetic response

6. Acetylcholine can be degraded/metabolized into a._______ to be recycled and b.______ to be excreted.

3 = ?

Calcium

ACETYLCHOLINE LIFESPAN:

1. ___________ comes from the Kreb’s Cycle

2. ____________________ enters the ganglion to produce Acetylcholine

3. Acetylcholine is put inside a __________ to protect it from degradation

4. An increase in ______ allows Acetylcholine to be released, moving it to the end of the ganglion.

5. Acetylcholine binds to ____________________ to produce a parasympathetic response

6. Acetylcholine can be degraded/metabolized into a._______ to be recycled and b.______ to be excreted.

4 = ?

cholinergic receptors

ACETYLCHOLINE LIFESPAN:

1. ___________ comes from the Kreb’s Cycle

2. ____________________ enters the ganglion to produce Acetylcholine

3. Acetylcholine is put inside a __________ to protect it from degradation

4. An increase in ______ allows Acetylcholine to be released, moving it to the end of the ganglion.

5. Acetylcholine binds to ____________________ to produce a parasympathetic response

6. Acetylcholine can be degraded/metabolized into a._______ to be recycled and b.______ to be excreted.

5 = ?

choline

ACETYLCHOLINE LIFESPAN:

1. ___________ comes from the Kreb’s Cycle

2. ____________________ enters the ganglion to produce Acetylcholine

3. Acetylcholine is put inside a __________ to protect it from degradation

4. An increase in ______ allows Acetylcholine to be released, moving it to the end of the ganglion.

5. Acetylcholine binds to ____________________ to produce a parasympathetic response

6. Acetylcholine can be degraded/metabolized into a._______ to be recycled and b.______ to be excreted.

6.a. = ?

acetate

ACETYLCHOLINE LIFESPAN:

1. ___________ comes from the Kreb’s Cycle

2. ____________________ enters the ganglion to produce Acetylcholine

3. Acetylcholine is put inside a __________ to protect it from degradation

4. An increase in ______ allows Acetylcholine to be released, moving it to the end of the ganglion.

5. Acetylcholine binds to ____________________ to produce a parasympathetic response

6. Acetylcholine can be degraded/metabolized into a._______ to be recycled and b.______ to be excreted.

6.b. = ?

Direct-Acting Cholinergic Agonists

Cholinergic Agonists promote Activation of Cholinergic Transmission either by:

• binds to cholinergic receptors, producing cholinergic activity

Choline Esters, Cholinomimetic Alkaloids

Examples of Direct-Acting Cholinergic Agonists

Indirect-Acting Cholinergic Agonists

Cholinergic Agonists promote Activation of Cholinergic Transmission either by:

• increasing acetylcholine present in the bloodstream by preventing its degradation

Edrophonium, Carbamates, and Organophosphates

Examples of Indirect-Acting Cholinergic Agonists

Muscarinic

Cholinergic receptors include:

a. receptors found in visceral organs.

b. found in the post-synaptic neuron of both sympathetic and parasympathetic ANS

c. found in the skeletal muscle

a = ?

Nicotinic neural

Cholinergic receptors include:

a. receptors found in visceral organs.

b. found in the post-synaptic neuron of both sympathetic and parasympathetic ANS

c. found in the skeletal muscle

b = ?

Nicotinic muscular

Cholinergic receptors include:

a. receptors found in visceral organs.

b. found in the post-synaptic neuron of both sympathetic and parasympathetic ANS

c. found in the skeletal muscle

c = ?

G-protein Coupled Receptors

MOA OF DIRECT-ACTING AGENTS:

• Muscarinic receptors are __________________________________

intracellular secondary messengers (Inositol Triphosphate or IP3, Diacyl Glycerol or DAG, and Cyclic Guanosine Monophosphate or cGMP)

MOA OF DIRECT-ACTING AGENTS:

• Muscarinic Agonist Agents will activate it and the effect is mediated by __________________________________________, leading to altered organ function

ligand-gated ion channels

MOA OF DIRECT-ACTING AGENTS:

• Nicotinic receptors are ________________________________ which have 2 agonist binding sites and are permeable to Na, K, and Ca ions

Excitatory Postsynaptic Potential (EPSP)

MOA OF DIRECT-ACTING AGENTS:

• Nicotinic Agonist Agents binds to receptors allowing Na influx (depol) producing an ______________________________________ which creates the action potential triggering contraction

acetylcholine

MOA OF Acetylcholinesterase (AChE):

1. Bind ______________ and hydrolyze it to acetyl-enzyme complex and free choline.

2. ____________________________ is hydrolyzed to free the enzyme.

1 = ?

Acetyl-enzyme complex

MOA OF Acetylcholinesterase (AChE):

1. Bind ______________ and hydrolyze it to acetyl-enzyme complex and free choline.

2. ____________________________ is hydrolyzed to free the enzyme.

2 = ?

Acetylcholinesterase (AChE)

MOA OF INDIRECT-ACTING AGENTS:

1. Drugs will bind the metabolizing enzyme __________________________ and prevents degradation of neurotransmitter

2. This indirectly _________________________________ available to bind to the receptor.

1 = ?

increases the levels of acetylcholine

MOA OF INDIRECT-ACTING AGENTS:

1. Drugs will bind the metabolizing enzyme __________________________ and prevents degradation of neurotransmitter

2. This indirectly _________________________________ available to bind to the receptor.

2 = ?

Choline Esters

DIRECT-ACTING CHOLINERGIC AGONISTS:

• A quaternary ammonium group is important for its activity

lipid insoluble (hydrophilic)

DIRECT-ACTING CHOLINERGIC AGONISTS:

• Choline esters are relatively a.__________________. As a result these drugs are b.__________________________ in the CNS.

a = ?

poorly absorbed and distributed

DIRECT-ACTING CHOLINERGIC AGONISTS:

• Choline esters are relatively a.__________________. As a result these drugs are b.__________________________ in the CNS.

b = ?

Acetylcholine

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• hydrolyzed easily by acetylcholinesterase so they have a very short half-life

Metacholine, Betanechol, and Carbachol

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• all resistant to acetylcholinesterase

prototype

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• Acetylcholine is the _________________

5-30 secs

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• DOA of Acetylcholine

eyedrops in Ophthalmology to constrict the pupil

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• Use of Acetylcholine

Negative chronotropy and Decrease blood pressure (DUMBVELS)

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• Side Effect of Acetylcholine

Betanechol

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• not hydrolyzed by AChE, although inactivated through hydrolysis through other esterases

• lacks Nicotinic action

30 mins

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• DOA of Betanechol

smooth muscle of the bladder and the GIT

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• site of action of Betanechol

Postoperative neurogenic ileus and Urinary Retention

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• Use/s of Betanechol

Carbanechol (Carbachol)

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• Muscarinic and Nicotinic (Receptor Non-Selectivity)

• ester of Carbamic Acid

• Biotransformed by other esterase

• High Potency

• Long DOA

Glaucoma by causing pupillary contraction

DIRECT-ACTING CHOLINERGIC AGONISTS:

CHOLINE ESTERS

• Carbanechol (Carbachol) Use

Cholinomimetic Alkaloids

DIRECT-ACTING CHOLINERGIC AGONISTS:

• these drugs do not share a structural similarity as that of acetylcholine but they are capable activating the same cholinergic receptors

• well-absorbed from the site of administration

Nicotine, Lobeline, and Pilocarpine

DIRECT-ACTING CHOLINERGIC AGONISTS:

• cholinomimetic alkaloids that only contains a tertiary amine group

Muscarine

DIRECT-ACTING CHOLINERGIC AGONISTS:

• cholinomimetic alkaloids that is less absorbed in the GIT can be toxic upon ingestion

CNS

DIRECT-ACTING CHOLINERGIC AGONISTS:

Cholinomimetic Alkaloids

• Nicotine has more effect in the ____________ than in the skeletal muscle.

Pilocarpine

DIRECT-ACTING CHOLINERGIC AGONISTS:

Cholinomimetic Alkaloids

• stable to hydrolysis by acetylcholinesterase

• less potent compared with acetylcholine and its derivative

• uncharged and will penetrate the CNS at therapeutic dose

• exhibits cholinergic activity

ophthalmology (glaucoma)

DIRECT-ACTING CHOLINERGIC AGONISTS:

Cholinomimetic Alkaloids

• Use of Pilocarpine

Nicotine

DIRECT-ACTING CHOLINERGIC AGONISTS:

Cholinomimetic Alkaloids

• agonists at both Nm and Nn receptor

• Activates autonomic post ganglionic neuron and skeletal muscles neuromuscular end plate

• enters CNS and activates Nn receptor

Smoking Cessation

Edrophonium

INDIRECT-ACTING CHOLINERGIC AGONISTS:

• An alcohol being a quaternary ammonium group that forms an electrostatic bond with AChE resulting to a reversible inhibition of the enzyme

10-20 minutes

INDIRECT-ACTING CHOLINERGIC AGONISTS:

• DOA of Edrophonium

diagnose (Tensilon’s Test) and treat Acute Myasthenia Gravis

Carbamates

INDIRECT-ACTING CHOLINERGIC AGONISTS:

• Most drugs are relatively insoluble in lipids and require large dose if given orally

• can also be metabolized by other cholinesterase enzyme

• binds covalently to the active site of AChE preventing access to the acetylcholine

Physostigmine

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Carbamates

• only well absorbed in all sites of administration and is more toxic than the other carbamates

Neostigmine

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Carbamates

Physostigmine

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Carbamates

• Eserine

• Nitrogenous carbamic ester usually found naturally and is a tertiary amine

• DOA: 2-4 hrs

Glaucoma, Anticholinergic Overdose

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Carbamates

• Use/s of Physostigmine

chronic management of myasthenia gravis

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Carbamates

• Use/s of Pyridostigmine

delays the progression of Alzheimer’s Disease

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Carbamates

• use/s of Rivastigmine

Lipid Soluble Insecticide

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Carbamates

• use/s of Carbaryl

Organophosphates

INDIRECT-ACTING CHOLINERGIC AGONISTS:

• highly lipid soluble and absorbed in the skin, lung, gut, and conjunctiva

• highly distributed even in the CNS and an important area during poisoning

• drugs contain a phosphate group (-PO4) which binds with AChE in an extremely stable covalent bond

• bonding process is similar with carbamates but the phosphorylated enzyme is more stable, hard to break, and hydrolyzes very slow

Echothiophate

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Organophosphates

• highly polar and stable in aqueous solutions

Bond aging

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Organophosphates

• unique with organophosphate and AChE interaction where an oxygen-phosphorus bond break to further strengthen the bond with the enzyme

Pralidoxime

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Organophosphates

• Bond Aging is prevented by giving an oxime regenerator such as:

open-angle glaucoma

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Organophosphates

• use/s of echotiophate

Soman, Sarin, & Tabun

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Organophosphates

• nerve gases (very toxic & lethal) which is used for chemical warfare

Malathion

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Organophosphates

• used as insecticide that can be metabolized by humans

Parathion

INDIRECT-ACTING CHOLINERGIC AGONISTS:

Organophosphates

• used as insecticide that is not effectively detoxified in humans and hence it is more dangerous