Cholinergic Agonist

Question 1

Cholinergic agonists are either direct or indirect acting, what is the difference?

Answer 1

Direct Agonist: bind to and activate muscarinic or nicotinic receptors
Indirect Agonist: act by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline and acetic acid.

Question 2

ACh has 4 primary direct effects on the cardiovascular system, what are they?

Answer 2

1. Vasodilation (M3)
2. Decrease in heart rate (M2)
3. Decrease in rate of conduction in the SM and AV nodes (M2)
   (via decrease in the amount of Ca2+ in the heart)
4. Decrease in force of contraction (M2)

Question 3

What would happen to a patient if they were injected by a small dose of acetylcholine?

Answer 3

Produces a fall in blood pressure due to generalized vasodilation (M3) accompanied by reflex tachycardia

Question 4

What would happen to a patient if they were injected by a large dose of acetylcholine?

Answer 4

Produces bradycardia and decrease conduction velocity through the A node (M2) in addition to causing vasodilation and hypotension mediated by M3

Question 5

There is no actual innervation of the vasculature by the parasympathetic system, so how does M3 cause vasodilation?

Answer 5

there are unninervated M3 muscarinic receptors on the endothelial cells of the vasculature.
–these M3 receptors mediate relaxation of vascular muscle via release of NO from endothelial cells

Question 6

Each card will list the effects of Acetylcholine on various organ systems, first the vasculature (endothelial cells)

Answer 6

M3

• -release of Nitric Oxide and Vasodilation (therefore drop in BP)
• -remember you only need a small amount of ACh injected to drop the BP

Question 7

2nd effect of ACh is on the eye iris?

Answer 7

M3

• -contraction
• -miosis (via pupillary sphincter muscle contraction)

Question 8

3rd effect of ACh is on the ciliary muscle?

Answer 8

M3

–contraction and accommodation of lens to near vision

Question 9

4th effect of ACh is on the salivary and lacrimal glands

Answer 9

M3

–watery secretions

Question 10

5th effect of ACh is on the bronchi

Answer 10

M3

–Constriction and increased secretions

Question 11

6th effect of ACh is on the Heart

Answer 11

M2

–bradycardia, decreased conduction velocity, AV block at high doses, and slight decrease in contractility

Question 12

7th effect of ACh is in the GI tract

Answer 12

M3

–increased tone, increased peristaltic activity, increased secretion and relaxation of sphincters

Question 13

8th effect of ACh is on the urinary bladder

Answer 13

M3

Contraction of detrusor muscle and relaxation of sphincter

Question 14

9th effect of ACh is on the sweat glands

Answer 14

M3
Diaphoresis (Remember that sweat glands are an exception to the rule they are sympathetic response not parasympathetic)

Question 15

10th effect of ACh is on the male reproductive tract

Answer 15

M3

Erection

Question 16

11th effect of ACh is on the uterus

Answer 16

M3

Variable

Question 17

Moving on to the actual drugs. First class of drugs are cholinergic agonists. The first drug is acetylcholine, what would be the use of this drug?

Answer 17

• -No systemic therapeutic applications because of its multiplicity of actions and rapid hydrolysis
• -use: obtain rapid miosis after delivery of the lens in cataract surgery

Question 18

The second cholinergic agonists is bethanechol, what is the use?

Answer 18

Tx:
1. acute postoperative and postpartum non obstructive urinary retention
2. neurogenic atony of the urinary bladder with retention
3. Postoperative ileus or neurogenic ileus
Activates bowel and bladder smooth muscle
Resistant to AChE

Question 19

In general what are the adverse effects of any cholinergic agonist?

Answer 19

Increased Parasympathetic effects

• sweating (sweat glands)
• salivation
• -flushing
• -low blood pressure (M2)
• -nausea
• -abd pain
• -diarrhea
• -bronchospasm

Question 20

The third cholinergic agonist is carbachol, what is the use?

Answer 20

Both muscarinic and nicotinic agonist

–constricts pupil (miosis) and relieves intraocular pressure in glaucoma

Question 21

The fourth cholinergic agonist is methacholine, what is the use?

Answer 21

Mostly muscarinic agonist

–diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma

Question 22

The last cholinergic agonist is pilocarpine, what is the use?

Answer 22

Partial muscarinic agonist

• -second line agent for open angle glaucoma
• -management of acute angle-closure glaucoma
• -Contracts ciliary muscle of eye (open angle glaucoma) and pupillary sphincter (Closed angle glaucoma)
• resistant to AChE
• –potent stimulator of sweat, tears and saliva

Question 23

The only nicotinic receptor agonist to speak about is Nicotine which is a ganglion stimulant. What are the actions of nicotine?

Answer 23

–Ganglionic stimulation by depolarization
initial response to nicotine therefore resembles simultaneous discharge of both the parasympathetic and sympathetic nervous systems

Question 24

What are the effects of nicotine in the heart, GI/Urinary tracts and Bronchial tract?

Answer 24

CVS: mainly sympathomimetic therefore increase in HR and blood pressure due to catecholamine release from adrenengic nerve terminals and from the adrenal medulla
GI/Urinary: parasympathetic: nausea, vomiting, diarrhea and voiding of urine
Salivary and Bronchial Secretions: parasympathetic

Question 25

At high doses nicotine can cause?

Answer 25

ganglionic blockade as a consequence of prolonged depolarization --also causes a neuromuscular blockade

Question 26

What are the symptoms of acute nicotine poisoning?

Answer 26

Nausea, salivation, abd pain, vomiting, diarrhea, cold sweat, mental confusion, and weakness --blood pressure falls, pulse is weak, rapid and irregular.

Question 27

Nicotine is highly liposoluble, which means what?

Answer 27

Absorption is fast via oral mucosa, lungs, GI mucosa, and skin --crosses placental membrane and is secreted in milk

Question 28

What is the use for nicotine?

Answer 28

smoking cessation therapy

Question 29

Moving on to the indirect acting cholinergic agonists (Anticholinesterases), what is the mechanism of action of these drugs?

Answer 29

Inhibit acetylcholinesterase and thereby increase the concentration of endogenous acetylcholine

Question 30

Cholinesterase inhibitors have less marked effects on vascular smooth muscle and on blood pressure than direct acting muscarinic agonists, why?

Answer 30

Because indirect acting drugs can modify the tone of only those vessels innervated by cholinergic nerves and because the net effect of vascular tone may reflect activation of both parasympathetic and sympathetic systems. --therefore since few vascular beds receive cholinergic innervation, the cholinergic effect at vascular smooth muscle is minimal.

Question 31

The first anticholinesterase is edrophonium, what is the use?

Answer 31

Dx of myasthenia gravis (Causes a rapid but short increase in muscle strength due to the increase in ACh)

Question 32

The second anticholinesterase is physostigmine, what are the uses?

Answer 32

Tx of overdoses of anticholinergic drugs | --penetrates the blood brain barrier and exerts central cholinergic effects

Question 33

What are adverse effects of physostigmine?

Answer 33

Lead to convulsions when high doses are used Bradycardia Inhibition of acetylcholinesterases at the NMJ causes accumulation of acetylcholine and results in paralysis of skeletal muscle.

Question 34

The third anticholinesterase is neostigmine, what is the use?

Answer 34

1. Reversal of effects of non-depolarizing neuromuscular blockers after surgery - -most commonly used drug for this indication 2. Used for symptomatic treatment of myasthenia gravis - -most commonly used is pyridostigmine though 3. Prevention and tx of postoperative distention and urinary retention

Question 35

The fourth anticholinesterase is pyridostigmine, what is the use?

Answer 35

1. Indicated for tx of myasthenia gravis | - -most commonly used anticholinesterase for this indication

Question 36

The next set of anticholinesterase drugs are the organophosphates, many are highly liposoluble and extremely toxic. The only one used clinically is echothioophate, what are the uses?

Answer 36

Used for chronic open angle glaucoma, subacute or chronic angle closure glaucoma after iridectomy or where surgery is refused.

Question 37

The two thiophosphate insecticides are malathion and parathion, what are the effects of each?

Answer 37

Malathion: considered safe enough for sale to the general public Parathion: not available for general public use due to the danger to humans and livestock

Question 38

What is the antidote for organophosphate poisoning?

Answer 38

Atropine (competitive inhibitor) | -muscarinic antagonists --- so prevents ACh from binding

Question 39

What is the pneumonic for organophosphate or any cholinesterase inhibitor poisoning?

Answer 39

``` DUMBBELSS D: diarrhea U: urination M: Miosis B: bronchospasm B: bradycardia E: excitation of the skeletal muscle and CNS L: lacrimation S: sweating S: salivation ```

Question 40

Finally the last organophosphates are the nerve agents, what are they?

Answer 40

Tabun, Sarin and Soman | --among the most potent synthetic toxic agents known

Question 41

All of the organophosphates, except echothiophate, are fully distributed to all parts of the body, including the CNS.

Answer 41

:)

Question 42

Finally the last set of drugs in the indirect agonist (Anticholinesterases) are the alzheimer drugs, what is the reasoning behind the use of these drugs in Alzheimers disease?

Answer 42

Donepezil, rivastigmine and galantamine - -patient have reduced cerebral production of choline acetyl transferase -- leads to decrease in acetylcholine synthesis - -these inhibitors attempt to compensate for the depletion of acetylcholine in the cerebral cortex and hippocampus

Question 43

Lastly Pralidoxime is used in AChE inhibitor toxicity, explain the mechanism

Answer 43

--reactivates inhibited acetylcholinesterase if given before ageing has occurred the drug can be used as cholinesterase regenerator drug for organophosphate insecticide poisoning --however this drug does not enter the CNS