Nicotinics & AChE

Question 1

What kind of receptors are Nicotinic Cholinergic Receptors (nAChRs)?

Answer 1

LGIC’s (Na+, Ca2+)

Question 2

In the somatic nervous system, what is the structure of nAChRs?

Answer 2

They are a Pentameric Structure.

Question 3

In the somatic nervous system where are the ACh binding sites located on the nAChRs?

Answer 3

Alpha interface

Delta/Epsilon interface.

Question 4

How many ACh molecules must bind to open the ion channel?

Answer 4

2

Question 5

What kind of nAChRs are located in the the Autonomic ganglia/Adrenal Medulla?

Answer 5

Alpha 3 containing.

Question 6

What kind of isoforms of nAChRs exist in the CNS?

Answer 6

Many receptor isoforms BUT alpha and beta subunits only.

Question 7

What is the most common alpha subunit in the CNS?

Answer 7

Alpha 4.

Question 8

Which alpha subunit of nAChRs has high levels of expression in brain DA neurons?

Answer 8

Alpha 6

Question 9

What is the second most common alpha subunit of nAChRs?

Answer 9

Alpha 7

Question 10

What is the alpha 7 subunit of nAChRs more permeable to?

Answer 10

Increase Ca2+ permeability.

Question 11

What alpha subunit of nAChRs is only expressed in the cochlea?

Answer 11

Alpha 9

Question 12

What are the Direct Acting Nicotinic Agonists?

Answer 12

1. Nicotine
2. Lobeline (indian tobacco)
3. Epibatidine (frog)

Question 13

Why are actions of nicotinic agonists complex?

Answer 13

1. Many potential sites of action.
2. Activation of receptors followed by prolonged desensitization
3. Nicotine a “secretagoge” - nAChRs on many types of presynaptic nerve terminals.

Question 14

What are the most common exposures that cause acute nicotine toxicity?

Answer 14

1. Pesticides
2. Children eat cigs
3. Harvesting tobacco
4. Smoking while using nicotine patch or ecig

Question 15

What can happen at a level of 40mg of nicotine?

Answer 15

Death due to:

1. convulsions
2. myocardial infarction
3. Respiratory failure.

Question 16

How do you treat nicotine overexposure?

Answer 16

1. Gastric lavage

2. Mecamylamine for convulsions

Question 17

What are symptoms of nicotine withdrawal?

Answer 17

1. Dizziness, Tremor, High BP
2. irritability, craving, anxiety, restlessness, difficulty concentrating.
3. IBS and increased appetite.

Question 18

What are pharmacological tools for smoking cessation?

Answer 18

1. NRT
2. Verenicline (chantix) - partial agonist
3. Bupropion
4. Clonidine
5. NicVax?
6. BMOD
7. Ecig?

Question 19

Does a nicotinic agonist or antagonist increase the number of receptors?

Answer 19

BOTH can.

Question 20

Where are Neuronal nictotinic receptors prominently located?

Answer 20

On the presynaptic nerve terminals.

Question 21

What does nicotine reinforce?

Answer 21

Voluntary inhalation of known carcinogens.

Question 22

What are Therapeutic actions of nicotinic agonists?

Answer 22

1. Parkinson’s
2. Alzheimer’s
3. Cognitive disorders
4. Schizophrenia/ADHD
5. Tourette’s
6. Ulcerative colitus
7. Anxiety/ Alcholoism
8. Analgesia
9. Obesity

Question 23

How do indirect acting skeletal muscle relaxants work?

Answer 23

By decreasing ACh release in somatic NS.

Question 24

How do direct acting skeletal muscle relaxants work?

Answer 24

Block muscle nAChRs
aka Paralytic drugs

Can be competitive and non-competitive.

Question 25

Do skeletal muscle relaxants affect the CNS or cross the placenta?

Answer 25

NO

Question 26

How to non-depolarizing neuromuscular competitive antagonists work?

Answer 26

Block agonist recognition site on alpha subunit.

Question 27

When using a non-depolarizing neuromuscular blocker, when will you see a effect?

Answer 27

when 75-80% of nAChRs are blocked.

Question 28

Non-depolarizing neuromuscular blockers can produce ganglionic blockade, what does that cause?

Answer 28

Hypotension | Reflex tachycardia.

Question 29

How is the effect of non-depolarizing neuromuscular blockers typically reversed?

Answer 29

with AChEIs

Question 30

Agonist binding to Nicotinic ACh receptors causes the channel to do what?

Answer 30

Block sodium influx into the cell.

Question 31

What is an example of depolarizing neuromuscular blockers?

Answer 31

Succinylcholine

Question 32

How does succinylcholine work?

Answer 32

Depolarizes the NMJ initially, then produces a longer lasting blockade of the ion channel.

Question 33

What does succinylcholine have affinity for?

Answer 33

1. Agonist recognition site - competitive (brief) | 2. Central ion channel - non-competitive (prolonged)

Question 34

Does succinylcholine invoke local histamine release?

Answer 34

NO it does not, it is a non-irritant.

Question 35

What is succinylcholine metabolized by?

Answer 35

Plasma cholinesterase ( + for rapid procedures; butyrl)

Question 36

what is blocked in phase 1 block of the NAChR?

Answer 36

The allosteric site where nicotine normally binds.

Question 37

What is blocked in phase 2 block of the NAChR?

Answer 37

The actual channel.

Question 38

What are adverse drug reactions of succinylcholine?

Answer 38

1. Postoperative muscle pain. 2. Hyperkalemia 3. Malignant hyperthermia

Question 39

What kind of drug is Mecamylamine?

Answer 39

Ganglionic Blocking Drug.

Question 40

What do ganglionic blocking drugs cause?

Answer 40

1. Decreased BP 2. Loss of CV reflexes 3. Severe orthostatic hypotension -->sncope 4. Constipation, urinary retention, dry mouth, cycloplegia 5. Ganglionic blockade causes PARTIAL mydriasis

Question 41

What are ganglionic blocking drugs in clinical trials for?

Answer 41

Anti-Depressant.

Question 42

What are therapeutic uses of Acetylcholinesterases (AChE)?

Answer 42

1. Recovery from COMPETITIVE NMJ blockers 2. Autoimmune myasthenia gravis 3. Atropine (or scopolamine) poisoning. 4. Tricyclic anti-depressant overdose 5. Cognitive improvement in dementia.

Question 43

When does acetylcholinesterase act as a high efficacy enzyme?

Answer 43

when in high abundance.

Question 44

What is a acetylcholinesterase?

Answer 44

A serine hydrolase located on the outer cell membrane of neurons (pre & postsynaptic) in the CNS & PNS. A globular protein w/ active center buried in interior.

Question 45

What is the concentration of AChE at synapses?

Answer 45

10-20X greater than that needed to activate ACh.

Question 46

How fast can a single active enzyme of AChE hydrolyze ACh?

Answer 46

10,000 molecules/ second.

Question 47

What is Butyrlcholinesterase important for?

Answer 47

Catabolism of: 1. Some xenobiotics 2. Inhalation anesthetics 3. Succinylcholine 4. Cocaine

Question 48

What Carbamates cross the BBB?

Answer 48

Donepezil | Galanthamine (also a nAChR APL)

Question 49

What Carbamates dont cross the BBB?

Answer 49

Pyridostigmine (MG, prophylaxis in PGW)

Question 50

What are Carbamates?

Answer 50

Acetylcholine esterase inhibitors.

Question 51

How are ADRs of AChEI's caused?

Answer 51

Indirect agonism of nicotinic and muscarinic cholinergic receptors (ANS + Somatic + CNS)

Question 52

What is Myasthenia Gravis and what does it cause?

Answer 52

An Autoimmune disorder that affects the NMJ. Causes grave muscular weakness.

Question 53

How is Myasthenia Gravis treated?

Answer 53

With AChEIs, Corticosteroids, plasma pharesis, thymectomy.

Question 54

What is Lambert Eaton Myasthenic Syndrome?

Answer 54

1. AB's to Ca2+ channels.

Question 55

What are Organophophates?

Answer 55

Irreversible Inhibitors of AChE --> nerve gas.

Question 56

What are the 4 nerve gases?

Answer 56

Tabun (GA) Sarin (GB) highly volatile Soman (GD) Viscous VX Stable

Question 57

What are the stages of OP Inhibition of AChE?

Answer 57

1. Formation of the Michaelis enzyme-substrate complex. 2. Phosphorylation of the enzyme on a serine residue. 3. "aging" of the complex is due to the attachment of a charged monophosphate group.

Question 58

What needs to be synthesized because the endogenous reactivation of the AChE enzyme is so slow?

Answer 58

A new enzyme to re-initiate AChE activity.

Question 59

What does OP poisoning cause?

Answer 59

1. Acute Cholinergic Crisis | 2. Activates CNS, SNS, PNS, Somatic NS.

Question 60

What are physiological things that happen from OP poisoning?

Answer 60

1. Miosis 2. Lacrimation 3. Bradycardia 4. Vomiting 5. Confusion 6. Convulsions 7. Sweating 8. Increased secretions 9. Neuromuscular weakness 10. Bronchoconstriction 11. loss of sphincter control 12. anxiety

Question 61

What are usually the first signs of OP exposure?

Answer 61

Eye and Respiratory irritation.

Question 62

What are the most severe manifestations of OP exposure?

Answer 62

1. Bronchial constriction 2. Increased pulmonary secretions 3. Paralysis of the diaphragm and respiratory muscles. 4. Paralysis of the respiratory control center in CNS.

Question 63

What is the Treatment of OP Poisoning?

Answer 63

1. Immediate supportive measures - termination of exposure, gastric lavage, 100%O2, mechanical ventilation. 2. Atropine to block muscarinic post-synpatic responses. 3. Oximes - nucleophilic agents, 2PAM facilitate reactivation of enzyme. Must be before "aging" 4. Anticonvulsants - BZ's decrease anxiety and convulsions.