Pharm Fall Ii Cholinergic Agonist & Cholinesterase Inhibitors

Front 1

what are hte Direct Acting Cholinergic Agonists

Back 1

1. Ach
2. Bethanechol: M selective. GI and GU effects
3. Pliocarpine: M selective. Increase sweat/spit
4. Cevimeline

5. Carbachol
6. Nicotine
7. Valenicline

Stimulate M and N receptors

Front 2

what are the cholinesterase inhibitors

Back 2

1. Edrophonium
2. Neostigmine
3. Physostigmine
4. Echothiophate
5. Organophosphate
6. Donepezil

7. Pralidoxime (2PAM)

Front 3

what type of Drug?

1. Organophosphate
2. edrophonium
3. Varenicline
4. Nicotine
5. Carbachol
6. Donepezil
7. Echothiophate
8. Phyostigmine
9. Ach
10. Bethanechol
11. Edriohonium
12 Neostigmine
13. Pliocarpine
14. Cevimeline
15. Pralidoximine

Back 3

1. Organophosphate: ChE inhibitor
2. edrophonium: ChE inhibitor
3. Varenicline: Cholinergic Agonist
4. Nicotine: Cholinergic agonist
5. Carbachol: Cholinergic agonist
6. Donepezil: ChE inhibitor
7. Echothiophate: ChE inhibitor
8. Phyostigmine: ChE inhibitor
9. Ach: Cholinergic agonist
10. Bethanechol: Cholinergic Agonist
11. Edriohonium: ChE inhibitor
12 Neostigmine: ChE inhibitor
13. Pliocarpine: Cholinergic agonist
14. Cevimeline: Cholinergic agonist
15. Pralidoximine: 2 PAM,

Front 4

Muscarinic stimulation affects what areas of the body

Back 4

its like PNS stim in the...

1. Eye: M3, constriction, accomadation, contract ciliary mm --> decreased intraocular pressure

2. GI: M3 stim GI motility/secretion, relax sphincters

3. Bladder: M3, contract bladder, relax sphincter, erection

4. Saliva: M3

5. Sweat (SNS) M1

*M3, bronchoconstriction
*M2 slow heart
* M agonist will release NO for BV dilation

M1/M3- increase PLC --> IP3 + DAG (a1 too)

M2 decrease cAMP (a2 also)

Front 5

where are nicotinic R, what is their nature

Back 5

1. Autonimic ganglion
2. brain
3. Skeletal mm

Na channels, depolarize when open
Desensitize easily

Front 6

what are the direct and indirect cholinergic agonists

Back 6

1. Direct acting, bind to M or N receptor

2. Cholinesterase inhibitor, cant break Ach down so there is more around and its effects are potentiated

Front 7

Ach

Back 7

Direct Acting Cholinergic Agonist
Stim M and N receptors

*IV infusion gives PNS effects but we also have M3 stim, this makes NO and vasodilates

*metabolized too fast to have clinical effect

Front 8

what are the 2 main classes of M agonists

Back 8

1. Choline Esters
-Carbachol: stim M and N
-Bethanechol: stim M only (poor oral abs, wont enter CNS, good for GI, GU)

2. Alkaloids
-pilocarpine: stim M, well abs, gets in brain. Stim sweat and saliva
- NIcotine:
-Varenicline: partial N agonist

Front 9

Ach

Back 9

stimulate M and N, direct

IV infusion gives PNS but decrease in BM bc M3 release NO for dilation

Front 10

Carcachol

Back 10

direct acting cholinergic agonist
Choline ester

*stim M and N

Front 11

bethanechol

Back 11

cholinergic agonist, direct acting
Choline ester


*specific for M receptros
*used for GI and UG (helps you pee/digest)
*poor oral abs
*wont enter brain

Front 12

Pliocarpine

Back 12

Muscarinic R agonist

*effects seen in sweat and salivary glands
*good oral abs
*enter brain
*no heart effect

**will constrict the pupil and pull the iris away from the ant chamer trabecular meshwork, this will decrease intraocular pressure

*used for glaucoma and dry mouth

Front 13

varenicline

Back 13

partial N agonist

Front 14

what happens in the eye with muscarinic receptor stimulation

Back 14

1. Meiosis (contract sphincter mm)

2. Accomidation, contract ciliary body, lens gets fat and round

3. decrease intraocular pressure bc iris pulls away from ant chamber and opens trabecular meshwork

Front 15

what does pliocarpine do for glaucoma

Back 15

M agonist

*the pupil constricts and the iris is pulled away, and opens the angle and decreases intraocular pressure

*also used to tx dry mouth

Front 16

what are the cardiovascular effects of muscarinic stimulation

Back 16

1. decrease HR in atrium, M2. conduction decreased

2. M2 also decrease release of NE, leads to further slowing (Presynaptic M2 decrease NE release)

3. M3 will release NO in BV and cause dilation

**drugs that are M agonists dont actually have cardioeffects

Front 17

do M agonist drugs have strong cardio effects? whats expected

Back 17

M2 will decrease HR
Presynaptic M2 will decrease NE to further slow the heart

M3 on BV will do vasodilation

Front 18

Methacholine

Back 18

Cholinergic agonist

**will cause bronchoconstriction via M3

**used to Dx asthma

Front 19

what are the effects of Muscarinic stim on bronchioles

Back 19

M3 will cause constriction

Cholinergic agonists, need to be careful with asthmatics bc it can keep them from breathing

Front 20

what are the effects of Muscarinic agonists on the GI, what drug

Back 20

M3 increase peristalsis, increase secretion, relax sphincters,

Bethanechol

Front 21

what are the effects of Muscarinic stim on the salivary glands, drug

Back 21

watch out drooley!

Pliocarpine will increase salivation and sweat (M specific agonist)

Front 22

what are the effects of M stimulation on the GU

Back 22

M3 help ya pee, contract detrusor, relax sphincter. increase pressure for good peeing

*bethanechol used to tx urinary retention

Front 23

what is the effect on glands with muscarinic stimulation

Back 23

M1 stimulation increases sweat

*pliocarpine really increases sweat (and spit)

Front 24

what are the 3 clinical uses of M agonists?

Back 24

1. Glaucoma- Pliocarpine, decrease intraocular pressure by contracting ciliary mm and pulling the pupil away from the angle and letting aq humor flow out

2. GI/GU: bethanechol. gets GI moving (after surgery, megacolon etc) also helps you pee

3. Dry Mouth- Pilocarpine used to stim M3 for salivation but also does M1 for sweat. Cevimeline is more selective for M3 so only increases salivation

Front 25

Cevimeline is used for what

Back 25

selective M3 agonist

**used to tx dry mouth

Front 26

what are side effects of Muscarinic Agonists

Back 26

1. Diarrhea
2. Abd cramps
3. Salivation / Sweating
4. blurred vision
5. bronchoconstriction
6. cutaneous vasodilation
7. bladder tightness

Front 27

what are the contraindications for M agonists

Back 27

Peptic Ulcer
Coronary insuffiency
Asthma

(bethanechol, pilocarpine, cevimeline)

Front 28

whats the effect of AchE inhibitors

Back 28

increase M and N stimulation

*N are particularly susceptible to desensitization

**particular effects are dependent on the main tone in tissue

Front 29

what happens in the brain with AchE inhibitors

Back 29

increased Ach

Stim of M1 and Nn

Low dose: improved memory/alertness
High dose: desensitize Nn and cause convulsions and respiratory arrest

Front 30

in what areas will AchE inhibitors act like a M agonist?

Back 30

in places where PNS tone is dominant

GI
GU
EYE
Respiratory

Front 31

what happens in the heart with AchE inhibitors

Back 31

PNS response

*decrease HR, CO and force of contraction

**when lots of Ach is at gang the N receptors will desensitize SNS and increase PNS

**no cholinergic innervation so no vascular effects

Front 32

what happens at NMJ with high and low doses of AchE inhibitors

Back 32

Low: increase strength of contraction. good for MG and reversing NM blockade in surgery

High: mm paralysis bc of desensitization of N receptors

Front 33

neostigmine

Back 33

AchE inhibitor

- poor oral abs
- wont enter BBB
- used to Tx MG, direct stim effect on NMJ

Front 34

Edrophonium

Back 34

AchE inhibitor

- wont cross BBB
- IV injection, short acting
- Dx of MG

Front 35

what is the drug used to dx MG

Back 35

edrophonium

**its an AchE inhibitor

Front 36

Physostigmine

Back 36

AchE inhibitor

- used in eye for glaucoma
- good abs, cross BBB. no systemic use

Front 37

donepezil, rivastigmine

Back 37

AchE inhibotor

- Tx Alzheimers
- good oral, cross BBB

Front 38

organophosphate- echothiophate

Back 38

AchE inhibitor

- used in eye for glaucoma emergency, keep angle open til you can have surgery
- no systemic abs

Front 39

organophosphates

Back 39

AchE inhibitor

- insecticide/ nerve gas
- lipid soluble, good abs
- irrecervible inhibitor of AchE

Front 40

what are some clinical uses of AchE inhibitors

Back 40

1. Glaucoma: pliocarpine, also cholinergic agonist

2. GI/GU: bethanechol

3. MG: neostigmine, pyridostigmine, ambenonium. Dx with edrophonium

4. Reverse NMJ blockade inducedi n surgery- neostigmine, edrophonium

Front 41

tell me about glaucoma and Cholinergis agonists, direct and indirect

open angle
closed angle

Back 41

increase Ach so that we have meiosis, accomadation

**when we pull the iris constricted it opens up that angle and we can have aq humor leave and decrease intraocular pressure

**pliocarpine (direct) for open angle glaucoma, will cause blurred vision

**closed angle tx with combo of pliocarpine and AchE inhibitor- phyostigmine, echothiophate. control til surgery can fix it

Front 42

what is the tx for MG (myesthenia gravis)

Back 42

MG: AB kill N receptors at NMJ. used AchE inhibitors to increase Ach

Chronic tx: neostigmine. short actine, administer several times a day. increases M effects also so can cause side effects, overcome side effects with M antagonist

Dx: Edrophonium, short action. If a person had MG they will be stronger when this is administered. Can also be used to monitor tx of MG- high or low doses will cause weakness so we monitor with this. If we give it and the person gets stonger the dose is too low, if the person gets worse the dose of neostigmine is too high

Front 43

how can we reverse the effects of NM blockade in surgery

Back 43

AchE inhibitors like neostigmine or edrophonium (short acting, can also be used to dx MG)

*if we increase Ach we can overcome the block

Front 44

Whats 2PAM

Back 44

it can be used to reverse the effects of organophosphates. Organophosphates bind to and inhibit AchE. Early on 2PAM will undo the damage but eventually it becomes a permanent and fatal inhibition. Carbamates (neostigmine/phyostigmien) don’t “age” (ie are reversible) and so using 2 PAM with them is controversial

Front 45

Are organophosphates reversible?

Back 45

It’s a cholinesterase inhibitor, its only reversible in the early stages but then ages to become irreversible. 2PAM can reverse it if its given early. Neostigmine, phyostigmine and edrophonium are all reversible.

Front 46

_____ are used as nerve gas and _______, they are ________ lipid soluble

Back 46

organophosphates, pesticides, highly. They are cholinesterase inhibitors

Front 47

How are neostigmine and phyostigmine similar and different? What about edrophonium?

Back 47

Carbamates that forms stable reversible bond with AchE.

Neostigmine- poor oral abs, no CNS effects

Phyostigmine- good oral abs and enters CNS. So not used systemically, use is limited to eye.

Edrophonium- only lasts like 5-10 min, must be injected. Dx Myesthemia gravis

Front 48

When might we want to increase the effects of Ach?

Back 48

When we have less response to Ach due to disease or reverse effect of neuromuscular blocks used in surgery. Think neostigmine prototype

Front 49

What class of drug: neostigmine, phyostigmine, edrophonium, echothiophate, organophosphate, donepezil

Back 49

cholinesterase inhibitors. Act indirectly to increase Ach effects by inhibiting its breakdown

Front 50

What is varenicline? I

Back 50

Partial N (a4b2) agonist that works in the brain. Decreases cravings for nicotine but causes nightmares and increased G

Front 51

What are 4 things we see with nicotine poisioning, what do we use to tx it?

Back 51

1. Convulsions (coma, respiratory arrest)

2. Vomit

3. MM contraction followed by paralysis

4. HTN/arrhythemia tx with atropine to block M receptors (not sure why), anticonvulsants, respiration

Front 52

What happens when nicotinic R at the NMJ are stim?

Back 52

Initial contraction then flaccid paralysis as the R desensitizes

Front 53

What happens with the heart when ganglionic N receptors are stim? What about GI

Back 53

Nicotinic stim at gang will increase post gang NT release as well as Epi release form adrenal medulla. Effects depend on dominant tone. Heart: NE/Epi increase SNS- increase HR & BP. GI/GU- PNS increased so lots of nausea, vomit, diarrhea and peeing lots

Front 54

What happens when N R at the ganglion are stim?

Back 54

Increased post gang NT release, like stim PNS and SNS as well as Epi release. Effect in tissue depends on dominant tone in the tissue. Heart: increased SNS- HR BP increase GI: increased PNS- vomit, nausea, diarrhea, increased urination

Front 55

We know there are N R in the brain, what do they do with low and high dose of N?

Back 55

Low dose will stim brain and increase alertness. High dose causes vomit, tremor, convulsion **increase dopamine release, addictive!

Front 56

What does a high dose or long term stim of N receptor do?

Back 56

Desensitization, the N R will no longer respond to stimulus (down regulate)

Front 57

What is a nicotinic receptor?

Back 57

Ion channe, when Ach binds Na enters the cell and depolarizes it

Front 58

Where are nicotinic receptors located? What drug acts on them?

Back 58

Autonimoc ganglia, Sk mm, Brain. Ach binds. ALL presynaptic release Ach and act on nicotinic receptors

Front 59

what does it look like if we have AchE inhibitor TOXICITY/POISION

Back 59

SLUDGE

Salivation
Lacrimation
Urination
Defecation
Gastric Distress
Emesis

Miosis, sweat, bronshoconstriction, nausea, vomit, diarrhea, bradycardia, hypotension

initial mm contraction followd by paralysis, can lead to respiratory distress--> death if not tx

CNS can cause confusion, slurred speech, convulsions

Tx with atropine (M antagonist) or 2 PAM (pralidoxime)

Front 60

if you inhale nerve gas to a toxic level where do we see effects

what about oral

Back 60

nerve gas an an AchE inhibitor, will lead to PNS overstim

- eye will have miosis and respiratory system constricts


Oral: GI sx firs, decrease BP with compensatory increasein SNS

Front 61

how can we tx the effects of AchE inhibitor poision

Back 61

this is a massive Ach increase

block by M antagonist- Atropine
2 PAM for organophosphates

Front 62

whats SLUDGE

Back 62

signs of AchE toxicity

Salivation
Lacrimation
Urination
Defecation
Gastric disress
Emesis

**all the PNS stim from increased Ach

tx with atropine, M antagonist