Cholinergic Agonists

Question 1

Neurotransmission in cholinergic neurons involves 6 sequential steps name them

Answer 1

• Synthesis
• Storage
•Release
•Binding to receptors.
•Degradation of Ach in synaptic cleft
•Recycling of choline and acetate

Question 2

How can we block the release of AcH

Answer 2

This release can be blocked by botulinum
toxin

Question 3

What do some spider venoms do to AcH

Answer 3

the toxin in black widow spider venom causes all
the ACh stored in synaptic vesicles to empty into the synaptic gap.

Question 4

What are the families of cholinoceptors

Answer 4

• muscarinic receptors
• nicotinic receptors

Question 5

How are the mascurinic and nicotinic receptors were distinguished from each other?

Answer 5

Muscarinic receptors belong to the class of G-protein–coupled receptor,in addition to
binding ACh, also recognize muscarine, an alkaloid in certain poisonous mushrooms. By contrast, the muscarinic receptors show only
a weak affinity for nicotine, has five types M1-5,

Nicotinic receptors addition to binding ACh, also recognize nicotine but show only a weak affinity for muscarine, ligand-gated ion channels, two types, Nm And Nn

Question 6

what are the most common type of uscarinic receptors

Answer 6

m1 m2 m3

Question 7

what are the locations of the muscarinic receptors

Answer 7

post ganglionic parasympathetic organs
M1—— gastric parietal cells (GIT)
M2—— the heart and smooth muscles
M3—— bladder, glands and smooth muscles

Question 8

what is the mechanism of muscarinic receptors ACH signal transductions

Answer 8

M1 and M3——-the activate Gq protein

Gq leads to the production of IP3 and DAG second messengers

IP3—–increases intracellular CA+2 ——-hyper polarizaion

DAG——activates protein kinase C, an enzyme that phosphorylates proteins within the cell.

M2——- activates Gi protein

Gi —-that inhibits adenylyl cyclase and increases
K+ conductance—- heart rate decreases

Question 9

remember

Answer 9

M1 and M3—— increases the functions —–K+ closed——excitaion

m2———- decreases——k+ opened—-inhibition

Question 10

give an example on a non selective muscaraninic agonist

Answer 10

Pilocarpine is a nonselective muscarinic
agonist used to treat xerostomia and glaucoma.

Question 11

M1 receptor agonists are being investigated for the treatment of Alzheimer’s disease

 M3 receptor antagonists for the treatment of COPD.

What about M4 and M5 receptors?

No clinically important drugs interact solely with these
receptors

Answer 11

in CNS ok? ok

Question 12

about nicotinic receptors, what are the following
1- types
2- subunits and class of receptors
3- how many molecules needed to be active
4- what ions enter?
5- locations

Answer 12

1-Nm at neuro-muscular junction and Nn at CNS

2- composed of five subunits, and it functions as a ligand-gated ion channel (ionotropic receptor)

3- 2 molecules of ACH

4- Na+, causing depolarization

5- all presynaptic membranes, all somatic receptors, some CNS pathways

Question 13

what is a direct acting cholinergic agonists

Answer 13

Cholinergic agonists mimic the effects of ACh by binding directly to cholinoceptor

Question 14

what are the groups of direct acting cholinergic agonists

Answer 14

1) Endogenous choline esters, which include ACh

2) Synthetic ester of choline carbachol and bethanechol.

3) Naturally occurring alkaloids, such as nicotine and pilocarpine.

Question 15

What is the difference of these synthetic agonist from ACh?

Answer 15

they all have a longer duration

Question 16

Pilocarpine & bethanecol (therapeutically useful drugs) ?

Answer 16

yes but as a group, the directacting agonists show little specificity in their actions, which limits clinical usefulness

Question 17

about ACH answer the following

1- why does it lack therapeutic importance
2- whats the effect on HR and cardiac output
3- whats the effect on PB in details
4- whats the effect on GIT and bronchiolar secretions
5-whats the effects on the eyes

Answer 17

1- because of its multiplicity of actions (leading to diffuse effects) and its rapid inactivation by the cholinesterase

2-reduction in heart rate and output as a result of a reduction in the rate of firing at the SA node.

3- causes vasodilation indirectly by activating M3 receptors in the lining of smooth muscles of the blood vessels which increses nitric oxide, which causes the effect, without the IV ach those receptors have no job

4-it increases all secretions, and GIT motility, bronchoconstriction, the tone of detrusor muscles of the bladder (causing uniration).

5-stimulation of ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle, causing miosis (smaller pupil)

Question 18

about bethanechol answer the following
1-is it natural or synthetic, is it selective?
2- why is it not hydrolyzed by AChE
3- whats the duration
4- whats the effects
5- what are the uses
6- what are the adverse effects

Answer 18

1- its synthetic and selective to mascuranic

2-due to the esterification of carbamic acid

3- one hour

4- increased intestinal motility and tone. It also stimulates the detrusor muscle of the bladder, whereas the trigone and sphincter muscles are relaxed. These effects stimulate urination.

5- urologic treatment yin postpartum or postoperative, nonobstructive urinary retention and treat neurogenic atony as well as megacolon

6-nausea,abdominal pain, diarrhea, and bronchospasm sweating, salivation, flushing, decreased blood pressure (over come by atropin)

Question 19

about carbachol
1-is it natural or synthetic, is it selective?
2- whats the duration
3- whats the effects
4- what are the uses
5- what are the adverse effects

Answer 19

1- synthetic and non selective

2- long durations

3- has profound effects on both the CVS and the GI system because of its ganglion-stimulating activity.can cause release of epinephrine from the adrenal medulla by its nicotinic action, the eye, it mimics the effects of ACh, causing miosis and a spasm of accommodation in which the ciliary muscle of the eye remains in a constant state of contraction

4- Because of its high potency, receptor nonselectivity, and relatively long duration of action, carbachol is rarely used. Intraocular use provides miosis for eye surgery and lowers intraocular pressure in the treatment of glaucoma

5-With ophthalmologic use, few adverse effects
occur due to lack of systemic penetration

Question 20

about pilocarpine
1-is it natural or synthetic, is it selective?
2- whats the duration
3- whats the effects
4- what are the uses
5- what are the adverse effects

Answer 20

1-its natural and nonselective, less potent, can enter CNS and gets effected by AChE

2- depeds eg in the eye 4-8 hours

3- the eye, pilocarpine produces rapid
miosis, contraction of the ciliary muscle, and spasm of accommodation. Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva

4-treat glaucoma and is the drug of choice for emergency lowering of intraocular pressure of both open-angle and angle-closure glaucoma. promoting salivation in patients with xerostomia resulting from irradiation of the head and neck. Sjogren syndrome, which is characterized by dry mouth and lack of tears.

5-cause blurred vision, night blindness, and brow ache. Poisoning with this agent is characterized by exaggeration of various parasympathetic effects, profuse sweating (diaphoresis) and salivation. The effects are similar to those produced by consumption of mushrooms of the genus lnocybe.

Question 21

about the indirect- acting cholinergic agonists (reversible anti-AChE)
• How these drug act as cholinergic
agonists?
• Which cholinergic receptors will be
stimulated ?
• Are these drugs selective agonists?

Answer 21

1-by preventing the degradation of ACh. This
results in an accumulation of ACh in the synaptic space. Therefore, these drugs can provoke a response

2-both muscarinic and nicotinic receptors of the ANS, as well as at the NMJ and in the brain

3- nonselective

Question 22

about Edrophonium ( the prototype)

1- is it short or long acting
2- whats the duration
3- what are the uses

Answer 22

1- short acting

2- 10-20 mins dues to renal elimination

3- • It is used in the diagnosis of myasthenia gravis.
• autoimmune disease caused by antibodies to the nicotinic receptor at NMJs.
• This causes their degradation, making fewer receptors available for interaction with the neurotransmitter
• IV injection leads to a rapid increase in muscle strength.

Question 23

about physostigmine

1- how does it differ from edrophonium
2- what are the uses
3- what are the side effects

Answer 23

1-can enter the CNS

2-•Atony of intestinal and bladder, increases the motality
•treatment of overdoses of drugs with anticholinergic actions, such as atropine,
•reverse the effects of NMB

3- High doses of physostigmine may lead to convulsions. Bradycardia and a fall in cardiac output may also occur.
Inhibition of AChE at the NMJ causes the accumulation of ACh and, ultimately through continuous depolarization, results in paralysis of skeletal muscles

Question 24

about neostigmine

1- is it more polar? how does it effect the absorption
2-uses?
3-side effects?

Answer 24

1- more polar, it cant be absorbed into the CNS, has a greater effect on the skeletal muscles (can causes paralysis)

2-o stimulate the bladder and Gl tract
and as an antidote for competitive neuromuscular-blocking agents. Neostigmine is also used to manage symptoms of myasthenia
gravis.

3-same as physostigmine but m. Neostigmine does not cause CNS side effects and is not used to overcome toxicity of central-acting antimuscarinic agents such as atropine

Question 25

about pyridostigmine and ambenomium
what are the uses, duration and side effects

Answer 25

chronic management of myasthenia gravis. Its
duration of action is intermediate (3 to 6 hours) but longer than that of neostigmine. Adverse effects are similar to those of neostigmine.

Question 26

about Tacrine, donepezil, rivastigmine, and galantamine
what are the uses and side effects

Answer 26

to delay the progression of Alzheimer disease, none can stop its progression. Gl distress is their primary adverse effect

note* tacrine has hepatotoxicity

Question 27

what are irreversible Anti-AChE

Answer 27

A number of synthetic organophosphate compounds have the ability to bind covalently to AChE.they are extremely toxic and are used as weapons by the military

Question 28

about echothiophate

what is the MAO

what are the actions

what are the uses

Answer 28

1-binds to the enzyme active site and completely stops it from working, (new ones should be produced) the enzyme goes through di-ethylation ——–making it impossible for the pralidoxime to reactivate it

2- general cholinergic stimulation, paralysis, miosis, fall in the eye pressure.

3- for open angle glucoma

Question 29

what is the most common use for the irrevesible AChE inhibtors

Answer 29

poising, insecticides,Organophosphate nerve gases such as sarin are used as agents of warfare and chemical terrorism

Question 30

what are the toxic signs and symptoms of irrevesible AChE inhibitors

Answer 30

nicotinic and muscarinic signs and symptoms (cholinergic crisis}.
Depending on the agent, the effects can be peripheral or can affect the whole body

Question 31

talk about Reactivation of acetylcholinesterase

Answer 31

Pralidoxime can reactivate inhibited AChE by The presence of a charged group allows it to approach an anionic site on the enzyme, where it essentially displaces the phosphate group of the organophosphate and regenerates the enzyme(before aging)

it cant go through CNS

Question 32

name other treatments for irreversible AChE inhibtors poising

Answer 32

Atropine is administered to prevent muscarinic side effects of these agents. Such effects include increased bronchial and salivary secretion, bronchoconstriction, and bradycardia. Diazepam is also
administered to reduce the persistent convulsion caused by these
agents