test 3 part 2

Question 1

Acetylcholine Sites of Action

Answer 1

Preganglionic fibers
         Adrenal medulla
         Parasympathetic ganglia
         Sympathetic ganglia
Postganglionic fibers
         Parasympathetic
         Sympathetic sweat glands
Skeletal muscles of somatic system

Question 2

Step 1 of cholinergic neurotransmission

Answer 2

 Choline is actively transported from ECF into neuron via sodium cotransporter
 Carries a permanent positive charge and cannot diffuse
 Choline combines with acetyl coenzyme A to form ACh in the cytosol

Question 3

what is the rate-limiting factor step in ACh synthesis

Answer 3

• The uptake of choline into the neuron

Question 4

Step 2 of cholinergic neurotransmission

Answer 4

 Packaging and storage into presynaptic vesicles
 Active transport coupled to efflux of protons
 Vesicle contains Ach and cotransmitters ATP and proteoglycan

Question 5

Step 3 of cholinergic neurotransmission

Answer 5

 Voltage-sensitive calcium channels open when action potential arrives causing an increase in intracellular calcium
 Calcium promotes fusion of vesicle with the cell membrane
 ACh is released

Question 6

Step 4 of cholinergic neurotransmission

Answer 6

 ACh crosses the synaptic cleft and binds to receptors
 Target cell
 Membrane that released Ach
 Binding leads to biologic response

Question 7

Step 5 of cholinergic neurotransmission

Answer 7

 ACh is rapidly degraded

 Acetylcholinesterase (AChE) cleaves ACh to choline and acetate in the cleft

Question 8

Step 6 of cholinergic neurotransmission

Answer 8

 Sodium cotransport carries choline back into the neuron

 Choline is recycled

Question 9

Muscarinic Receptors and location

Answer 9

G protein-coupled receptors (cascade of intracellular events)
Recognize muscarine, an alkaloid present in poisonous mushrooms
Located in plasma membrane of all effectors innervated by parasympathetic postganglionic neurons (smooth muscle, cardiac, and glandular tissue)
Activation mimics the effect of the parasympathetic nervous system “parasympathomimetic” (mimics parasympathetic mechanism) (agonist)

Question 10

Muscarinic Receptor Subtypes

Answer 10

5 subtypes exist and all 5 are found on neurons
-OTHER LOCATIONS:
M1 - gastric parietal cells
M2 - cardiac cells and smooth muscle
M3 - bladder, exocrine glands, smooth muscle
- Muscarinic drugs preferentially stimulate these tissues, but at high concentrations may show some activity at nicotinic receptors

Question 11

Muscarinic Activation

Answer 11

• Consistent with “Rest and Digest” or ‘feed and breed”
• parasympathetic stimulation
  - constrict pupils
  - constrict bronchial musles
  - increase GI tract and bladder
  - decrease HR and contractility
  - gland secretion

Question 12

Nicotinic Receptors and location

Answer 12

Ligand-gated ion channels (ACh binds = ion channels open and influx of ions)
 Binding of 2 ACh molecules open channels which allow Na entry
 Depolarization of effector cell
Recognize nicotine
Low concentration: stimulates receptor
High concentration: blocks the receptor
Located in
 CNS
 Adrenal medulla
 Autonomic ganglia
 NMJ skeletal muscle

Question 13

Direct acting drugs

Answer 13

-agonists binds directly to the receptor

Question 14

Indirect-acting drugs

Answer 14

-block acetylcholinesterase (block the breakdown of ACh so that is how they produce their effect) allowing ACh to stay there longer

Question 15

Nicotine

Answer 15

• at low doses is an agonist => stimulates central nervous system getting a release of catecholomines
• very lipophilic => so actively absorbed
• at high doses is an anatagonist (60 mg)

Question 16

Carbachol (Miostat)

Answer 16

Direct Acting Muscarinic & Nicotinic Agonist
Nonselective nicotinic and muscarinic agonist
-Not used systemically because of this broad effect
Produces miosis (constriction) during surgery
Used topically to reduce intraocular pressure in glaucoma or post surgery

Question 17

Bethanechol (Urecholine)

Answer 17

Direct Acting Muscarinic Agonists
Major action on smooth muscle of bladder and GI tract
Produces urination
Short duration of action
-side effect = general cholinergic stimulation

Question 18

Pilocarpine (Salagen)

Answer 18

Direct Acting Muscarinic Agonists
Less potent than bethanechol (Urecholine) but can penetrate CNS at therapeutic doses
Topically to eye for miosis and reduction in intraocular pressure
Potent stimulator of secretions: sweat, tears, saliva
Sjögren’s syndrome: dry mouth and eyes

Question 19

Direct Acting Muscarinic Agonists and alzheimers disease

Answer 19

Currently being investigated for the treatment of Alzheimer’s disease
-muscurinic receptors on the neurons

Question 20

Indirect Acting Reversible Cholinergic Agonists

Answer 20

Reversibly binds to AChE to prevent degradation of Ach
ACh accumulates in the synaptic space
Can provoke a response at ALL cholinoceptors in the body
Short acting

Question 21

Edrophonium (Enlon)

Answer 21

Indirect Acting Reversible Cholinergic Agonists
Short acting AChE inhibitor (10-20 minutes)
Used for diagnosis of myasthenia gravis
“Edrophonium Test”

Question 22

Myasthenia Gravis

Answer 22

Chronic autoimmune neuromuscular disease
Caused by antibodies to the nicotinic receptor of the NMJ so that ACh can’t have an effect
Fewer receptors available for interaction with ACh
Skeletal muscle weakness

Question 23

Physostigmine

Answer 23

Indirect Acting Reversible Cholinergic Agonists
Intermediate duration of action (30 min-2 hours)
Can enter CNS cholinergic sites
Treatment of:
Anticholinergic overdose
Glaucoma

Question 24

Neostigmine

Answer 24

Indirect Acting Reversible Cholinergic Agonists
Similar to Physostigmine, but more polar and CANNOT enter CNS
Greater effect on skeletal muscle
Stimulate bladder and GI tract
Antidote for neuromuscular blocking agents (like those used in surgery)
Management of Myasthenia gravis symptoms

Question 25

Pyridostigmine

Answer 25

Indirect Acting Reversible Cholinergic Agonists
Chronic management of Myasthenia gravis
Duration 4-6 hours

Question 26

Indirect Acting Reversible Cholinergic Agonists and alzheimers

Answer 26

Some are currently being used to delay the progression of Alzheimer’s disease
None stop the progression

Question 27

Organophosphates

Answer 27

Indirect Acting IRREVERSIBLE Cholinergic Agonists
Bind to active site of AChE and permanently inactivate it until body regenerates it
Restoration of AChE requires new synthesis
Actions: generalized cholinergic stimulation, paralysis, breathing difficulties, convulsions
Once used topically for glaucoma (worldwide shortage) ECHOTHIOPHATE

Question 28

Organophosphate Poisoning

Answer 28

S alivation
L acrimation
U rination
D iarrhea
G I upset
E mesis

Question 29

Sarin Gas Exposure Immediate Signs and Symptoms

Answer 29

-sympathetic system in overdrive

Question 30

Organophosphate Poisoning Therapy

Answer 30

Pralidoxime (2-PAM)
        Can reactivate AChE
        Cannot penetrate CNS
Atropine
        Competitively binds to muscarinic receptor and block it from being binded to the ACh (competitive antagonist)