Cholinergic Agonists

Question 1

Cycle of ACh

Answer 1

1) made from acetyl-CoA+choline
2) ACh stored in neruons (quanta)
3) Release of ACh when neruons stimulated by an action potential
4) bind to ACh receptors
5) AChE breaks down ACh
6) acetyl-CoA and choline are recycled

Question 2

Two types of receptors that bind ACh

Answer 2

Muscarinic receptors

nicotinic receptors

Question 3

Muscarinic Receptors

Answer 3

are at the effector organ level of parasympathetic nervous system
no muscarinic receptors on the sympathetic side

Question 4

Nicotinic Receptor

Answer 4

at the ganglionic level of the parasympathetic side and sympathetic side of autonomic NS

bind ACh released from pre-ganglionic and pass to post ganglionic neurons

no inhibitory capabilities-only relay efferent messages sent from CNS

Question 5

2 Roles of ACh at Muscarinic Receptors in Parasymathetic NS

Answer 5

1) ACh is released that ACTIVATES muscarinic receptors on target organs (alters organ function by creating a positive stimulus ex contraction of muscle)
2) ACh is released and binds to receptors on nerve terminals to inhibit release of other NT’s (alters organ function by creating negative stimulus (ex relaxation of muscle)

Question 6

Role of ACh at Nicotinic Receptors in the Somatic NS

Answer 6

nicotinic receptors present at neruomuscular jxn of skeletal muscles

ACh (or agonist) binding=depolarization of nerve cell=positive stimulus (muscle contraction)

Prolonged binding to receptor causes postganglionic neuron to stop firing=skeletal muscle relxes and prevents further depolarization=muscle paralysis (negative stimulus)

Question 7

Cholinomimetic Agnet

Answer 7

Nonacetylcholine compound that mimics actions of ACh

Question 8

Cholinomimetic Agents as stimulants (direct agonists)

Answer 8

directly bind to ACh receptors (mimic ACh and bind to receptors)

Question 9

Cholinomimetic Agents as AChE inhibitors (indirect agonists)

Answer 9

indirect cholinergic action by inhibiting break down of ACh, ACh will stay in synapse longer and will continue to produce cholinergic action….same action as if you gave more ACh

Question 10

Types of Muscarinic Receptors

Answer 10

M1, M2, M3, M4, M5

M1, M3, M5–>cellular excitation (+ response)
M2, M4–>inhibit cellular excitability (-response, relaxation)

compounds will bind as either agonists or antagonists (agonsits will get effect you want plus side fx)

Question 11

Where are Muscarinic receptors founds

Answer 11

Mainly on autonomic effector organs

heart, smooth muscle, brain, exocrine glands

Question 12

Types of Nicotinic Receptors

Answer 12

Nm–neuromuscular junction

Nn–nicotinic receptors in any other location (CNS, adrenal medulla, autonomic ganglia)

Question 13

Direct Acting Cholinomimetics

Answer 13

Esters of Choline
Ex: acetylcholine

Alkaloids (compounds often taken from plants)
ex:muscarin and nicotine

Question 14

Choline Esters-Quarternary Ammoniums

Answer 14

makes insoluble lipid (quarternary nitrogen notrogen, wont get to the brain, cant cross BBB–dont usually have CNS problems)

Question 15

Characteristics of Quarternary Ammoniums

Answer 15

Hydrophilic (stay in soln and go where blood goes)

Hydrolyzed by AChE–affects their 1/2 life

Variations of structure alter binding affinity to receptors and susceptibility to hydrolysis by AChE

Question 16

Cholinomimetic Alkaloids

Answer 16

Tertiary Amines–CAN cross the BBB and cause CNS effects because it’s neutral charged

4 examples of cholinomimetic alkaloids:
Tertiary:
pilocarpine, nicotine, lobeline
Quarternary:
Muscarin (so it cant cross BBB cuz its + charge)

Question 17

Characteristicts of Cholinomimetic Alkaloids

Answer 17

• well absorbed orally
• lipid soluble–> allows for larger volumes of distribution
• Not susceptible to AChE

Question 18

Indirect Acting Cholinomimetic

Answer 18

act by inhibiting AChE

Question 19

Types of AChE inhibitors

Answer 19

simple alcohols– quarternary ammonium (edrophonium) able to inhibit AChE.

Carbamate esters– of alcohols with quarternary or tertiary ammonium (neostigmine, physostigmine, pyridostigmine)

Organophosphates (pestisides) (echothiophate, isofluorophate)

Question 20

Binding DIfferences Between AChE Inhibitors

Answer 20

Simple alcohols–> bind weakly and reversibly to AChE=shorter half-life of less than 10 mins

Carbamate Esters-bind reversibly but tighter to AChE=Prolonged half-life 30 minutes to 6 hours

Organophosphates–>covalent binding,extremely stable (nearly irreversible)= very long half-life of hundreds of hours

Question 21

Cholinomimetic Effects on Eye

Answer 21

contraction of iris sphincter smooth muscle=miosis (pupillary constriction)

contraction of ciliary muscle=responsile for focusing/accomidation

facilitate flow of aqueous humor out of anterior chamber so that you dont have buildup of aqueous fluid in posterior chamber–tx glaucoma

Question 22

Cholinomimetic Effect on Respiratory System

Answer 22

contraction of smoother muscle in bronchial tree, stimulates secretions from tracheobronchial mucosa

Question 23

Cholinomimetic Effects on the GI Tract

Answer 23

Increase secretory and motor activity- stimulates salivary and gastric gland secretions

increase peristalsis, relaxes GI sphincters allowsing GI contents to pass along tract

used to tx–>post op ileus congenital megacolan

Question 24

Cholinomimetic Effects on GU tract

Answer 24

stimulates detrusor muscle (contracts), and relaxation of trigone and sphincter muscles of bladder–> triggers voiding

tx urine retention (use bethanecol, neostigmine)

Question 25

Direct Cholinomimetics effects on Cardiovascular System (muscarinic agonists)

Answer 25

REDUCE PERIPHERAL VASCULAR RESISTANCE–> vasodilation reduces BP which causes an indirect reflex to increase HR (body’s compensatory mechanism)

also can decrease HR and reduces C/O

difficult to predict what it will do so ACh agonists aren’t used often in CV system

Question 26

Indirect Cholinomimetics effects on Cardiovascular System

Answer 26

AChE inhibitors=increase cholinergic activity in synapse

see same effects you see in muscarinic agonist
Negative chonotropic-bradycardia
Negative Inotropic-drop in C/O

modest drop in Bp

Question 27

Cholinomimetic Effect on Secretory glands

Answer 27

exaggerated muscarinic activity–> sweaty, tearing, increased mucous production/discharge from nose

Question 28

Direct Cholinomimetics on CNS: Nicotinic Receptors

Answer 28

induce tremor, stimulate emesis (vomiting), stimulate respiratory center

Question 29

Direct Cholinomimetics on CNS: Muscarinic Receptors

Answer 29

muscarin can’t cross the BBB, but there are muscarin receptors in the brain and muscarinic LIKE compounds can get to brain and trigger them

induce tremor, hypothermia, interfere w/nociception (ability of body to recognize toxin)

Question 30

Indirect Cholinomimetics effects on CNS

Answer 30

low concentration causes little effect

high concentration causes convulsions, coma, respiratory arrest

ex: exposure to organophosphates

Question 31

Use of Cholinomimetics for Alzheimers

Answer 31

AD=not enough receptors, soo tx with AChE inhibitors
AChE inhibitors–>ACh will hang around longer in the synapse and bind to more receptors
not curing but will slow progression

Ex:
tacrine, donepezil, galantamine, rivastigmine

Question 32

Use of Cholinomimetics with Smoking Cessation

Answer 32

Varenicline (chantix)–> direct nicotinic agonist, it will bind to nicotinic receptors in brain, decreases cravings and pleasurable effects of cigs

Question 33

Indirect Cholinomimetic Effects on Peripheral Nervous System

Answer 33

will cause discharge of sympathetic and parasympathetic nervous systems

Sympathetic–tachycardia or vagal induced bradycardia

Parasympathetic- GI, nausea, vomiting, diarrhea, urinary voiding

Question 34

ACh at Neuromuscular Junction

Answer 34

ACh is released and binds to NICOTINIC receptors on muscle fibers=depolarization=contraction of muscle

Question 35

Indirect Cholinomimetic effect on Neuromuscular Junction

Answer 35

AChE inhibitors
Low Dose-prolong effect of ACh=increased strenght

Medium Dose- muscle fibrillation=less effcitve use of muscle

High Dose= blocks muscle depolarization=paralysis

Question 36

Use of Cholinomimetics to Tx Mysthenia Gravis

Answer 36

increase muscle fxn
Mysthenia Gravis- antibodies bind to receptors and block ACh binding…give AChE inhibitor that allows ACh to have more time in synapse and find receptors to bind to that aren’t being blocked by antibody

doesnt cure but improves muscle fxn

Question 37

Use of Cholinomimetics Reverse Neuromuscular Paralysis

Answer 37

neostimine

Question 38

Use of Cholinomimetics to Tx Anticholinergic Intoxification

Answer 38

excessive anticholinergics–>dont eleict response they just sit on the receptor and block it–>cause arrhythmias

give AChE inhibitors like physostigmine to increase tje amnt of ACh at receptor sites

Question 39

Toxicity of Direct Muscarinic Agonists

Answer 39

N/V/D, urinary urgency. salivatiom, sweating, cutaneous vasodilation, bronchial constriction

tx with atropine and anticholinergics

Question 40

Toxicity of Direct Nicotinic Agonists

Answer 40

ex acute nicotine toxicity–>CNS stimulation, convulsions, coma, respiratory arrest, skeletal muscle depolarization, leading to blockade, respiratory paralysis. Htn and cardiac arrhythmias.

Question 41

Toxicity of Cholinesterase Inhibtors

Answer 41

Organophosphates and carna,ate cholinesterase inhibitors
symptoms–muscarinic excess (miosis, salivation, sweating, bronchial eonstriction, diaphragm paralysis, vomiting, diarrhea, convulsions)

Tx-antidote-parenteral atropine pr pralidoxime