Nicotinic cholinergics

Question 1

When can nicotine be poisonous and why do these people normally not die?

Answer 1

In children, who eat cigarette butts off their parents floor.

Generally, the emetic action of nicotine limits the amount absorbed

Question 2

What are the symptoms of nicotine poisoning?

Answer 2

Activation -> depolarizing blockade

1. Autonomic stimulation via the ganglia
2. CNS excitation with convulsions, followed by depression (from blockade)
3. Skeletal muscle paralysis from excessive stimulation

Question 3

What is varenicline and how is it used? What is its rare side effect?

Answer 3

Partial nicotinic receptor agonist, used in smoking cessation

Rare side effect: suicide

Question 4

How have neuromuscular junction ACh blockers revolutionized anesthesia?

Answer 4

Lower doses need to be used of general anesthesia, so patients don’t die. Can just immobilize their muscles and use enough to mentally sedate them

Question 5

What is the prototype competitive antagonist for nicotinic ACh receptors? What type of blockade is this?
How can these agents be counteracted?

Answer 5

d-tubocurarine (d-TC)

Non-depolarizing blockade

Agents can be counteracted by increasing ACh in the cleft to outcompete (Achase inhibitors)

Question 6

Before giving neostigmine for depolarizing blockade reversal, what is given first?

Answer 6

Atropine -> prevents the bradycardia, urination, and defecation associated with muscarinic ACh receptors (nicotinic at NMJ will still be reactivated)

Question 7

What is the main reason why tubocurarine is not used anymore, and what is the mechanism?

Answer 7

Rapid and transient fall in blood pressure for 2 reasons:

1. Sympathetic ganglion blockade reduces sympathetic tone of vascular system
2. d-TC stimulates histamine release from mast cells, which decreases peripheral resistance

Question 8

What is cisatracurium and why is it much more attractive of an option than d-TC?

Answer 8

Competitive nAChR antagonist, but only has mild hypotensive actions.

Much more attractive: spontaneously broken down with short half-life and thus safely used in patients with hepatic and renal failure

Question 9

What is the side effect of concern with cisatracurium?

Answer 9

One of its breakdown products crosses the BBB and can cause seizures (CNS excitation)

Question 10

What is pancuronium used for? In what way is it cross-reactive?

Answer 10

It is a nAChR competitive antagonist, with some M2 cross-reactivity (causes tachycardia)

Used in lethal injection

Question 11

What drug is structurally similar to pancuronium and why is it more attractive? How is it metabolized?

Answer 11

Vecuronium -> eliminated in bile (steroid-based, just like pancuronium, but pancuronium is eliminated renally)

More attractive because there is no M2 cross-reactivity

Question 12

What is Rocuronium used for and how is it similar to pancuronium and vecuronium?

Answer 12

Similar in that it’s steroid based -> eliminated in bile

Used for rapid-sequence intubation instead of Succinylcholine -> fastest onset of all three

Question 13

What drug causes depolarizing blockade of NMJ? What is its time-table? What type of drug is it?

Answer 13

Succinylcholine - agonist at NMJ, less than 1 minute onset of action, short duration

Drug type: competitive agonist (depolarizing blockade)

Question 14

How is succinylcholine metabolized and why is this a problem in some people?

Answer 14

Metabolized by plasma pseudocholinesterases after it diffuses out of the neuromuscular junction.

Some people have atypical plasma cholinesterases and if you are homozygous for this you will need a plasma transfusion which has this enzyme.

Takes longer if heterozygous

Question 15

Why should succinylcholine not be used in children?

Answer 15

May have an undiagnosed muscular dystrophy which upregulates nACh receptors, which can lead to an oversized response

-> main side effect is increase in blood potassium due to significant depolarization

Question 16

Given the main side effect of succinylcholine, what other patient populations should its use be avoided in?

Answer 16

extensive burns, trauma, people with K+ sparing diuretics or digitalis, or people with renal failure

• > all conditions where you would have high plasma levels of K+
• > Can cause cardiac arrest

Question 17

What is Phase 1 depolarizing blockade, and what can be used to antagonize it?

Answer 17

Slow increase in RMP to 0, above threshold, at which time the motor end plate is excited and causes at most one fasciculation before just staying depolarized

Nothing can antagonize it (acetylcholinesterases just make it worse)

Question 18

What is succinylcholine used for?

Answer 18

In emergency situations to facilitate intubation, or to relax neck and vocal cords so intubation can be done prior to general anesthesia

Question 19

What is pre-curarization?

Answer 19

Administration of rocuronium (non-depolarizing agent) prior to succinylcholine to prevent fasciculations
-> makes no sense in how it works

Question 20

What is phase 2 depolarizing blockade?

Answer 20

Prolonged use of succinylcholine will allow membrane to repolarize, and can actually be partially reversed via neostigmine (so weird, don’t know the mechanism)

Question 21

What type of amines are the skeletal muscle relaxants and how they administered?

Answer 21

All quaternary amines -> administered via IV (parenteral)

Do not cross BBB or placenta because of this

Question 22

What muscles are most and least affected by skeletal muscle blockade?

Answer 22

Most affected: digits, followed by neck & limbs

Least affected: Diaphragm and thorax -> but we still always intubate when we administer

Question 23

Is histamine release affected by cisatracurium and succinylcholine?

Answer 23

Yes, slightly

Not affected by pancuronium, rocuronium, or vecuronium

Question 24

How is dTC metabolized?

Answer 24

Eliminated in the kidney -> same as pancuronium

Question 25

What is the mechanism of action of dantrolene and what is it used for?

Answer 25

Blocks Ca+2 release from SR in skeletal muscles.

Two uses:

1. Treatment of malignant hyperthermia (which is caused by muscle spasm in anesthesia)
2. UMN spasticity in those wheelchair bound (will still keep them in wheelchair)

Question 26

What is the mechanism of action of baclofen and who is it given to?

Answer 26

GABA-B agonist, anti-spasmodic which is relatively non-sedating and does not produce as much generalized weakness as dantrolene

Question 27

What anti-spasmodic works as an atypical alpha-2 agonist? (pre- and post-synaptic nerve inhibition)

Answer 27

Tizanidine

Question 28

What is the MoA of Riluzole and what is it used for?

Answer 28

Inhibits glutamate signaling -> antispasmodic

Used to prolong life in ALS patients

Question 29

What is the name of the spasmolytic most frequently given as an anti-spasmodic by everyone? Mechanism of action unknown, but is definitely anti-muscarinic and sedative

Answer 29

Cyclobenzaprine

Question 30

What is the acetylcholine receptor primarily responsible for hyperpolarization?

Answer 30

M2 - Gi pathway

Question 31

What causes the slow excitation (EPSP) via acetylcholine?

Answer 31

Typically M1 receptors, or peptides.

The nicotinic receptor is very fast

Question 32

What is the mechanism of action of Mecamylamine? Is it a tertiary or quaternary amine?

Answer 32

Works via competitive antagonism of nAChR’s in postganglionic cell dendrites

It is actually a SECONDARY amine -> only one

Question 33

What is the primary reason ganglionic blocking drugs are not used?

Answer 33

Orthostatic hypotension -> due to lack of sympathetic tone in veins which prevent pooling of blood, along with a ton of different cholinergic atropine-like effects + impotence

Question 34

What did mecamylamine used to be used for, and what are its only uses now?

Answer 34

Used to treat hypertension due to blocking sympathetic tone to arterioles

Only used now for producing controlled hypotension in neurosurgery + nicotine-sensitive CNS disorders including Tourette’s