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Therapeutics > Exam 1 Cholinergic Agents > Flashcards

Exam 1 Cholinergic Agents Flashcards

1
Q

What are cholinergic agents?

A

parasympathetic mechanisms involving acetylcholine and their receptors (cholinergic receptors) and the neurotransmitter is acetylcholine (ACh)

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2
Q

What are the parasympathomimetic actions (agonists)?

A
  1. direct agonist → activates cholinoceptors

2. indirect agonist → stimulate acetylcholine release and inhibit acetylcholinesterase (AChE)

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3
Q

What are the parasympatholytic actions (antagonists)?

A

can be direct or indirect → many drugs exhibit anticholinergic side effects

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4
Q

What are the structural features of acetylcholine?

A

has an acetyl moiety and a choline group that is a quaternary amine so it has an intrinsic positive charge

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5
Q

What receptors does muscarine bind to?

A

it selectively binds to muscarinic receptors

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6
Q

What receptors does nicotine bind to?

A

it selectively binds to nicotinic receptors

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7
Q

What is the tissue distribution, responses, and mechanisms of Nm receptors (nicotinic muscular)?

A

tissue → skeletal muscle
response → motor end plate depolarization, contraction
mechanism → ligand gated opening of Na+/K+

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8
Q

What is the tissue distribution, response, and mechanism of Nn receptors (nicotinic neuronal)?

A

tissue → postganglionic & adrenal medulla
response → depolarization & catecholamine secretion
mechanism → ligand gated opening of Na+/K+

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9
Q

What is the tissue distribution, responses, and mechanisms of M1 receptors?

A

tissue distribution → postganglionic
response → depolarization
mechanism → Gq increase in PLC, IP3, DAG, Ca2+

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10
Q

What is the tissue distribution, responses, and mechanisms of M2 receptors?

A

tissue distribution → heart
response → inhibition
mechanism → Gi inhibition of adenylyl cyclase (cAMP), activation of K+ channels

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11
Q

What is the tissue distribution, responses, and mechanisms of M3 receptors?

A

tissue distribution → smooth muscles & exocrine glands & endothelium
response → contraction & secretion & relaxation
mechanism → Gq increase in PLC, IP3, DAG, Ca2+ && release of NO and increase in GC

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12
Q

What is the tissue distribution, responses, and mechanisms of M4 receptors?

A

tissue distribution → CNS
response → hyperpolarization
mechanism → Gi inhibition of adenylyl cyclase

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13
Q

What is the tissue distribution, responses, and mechanisms of M5 receptors?

A

tissue → CNS
response → depolarization
mechanism → Gq increase in PLC, IP3, DAG, Ca2+

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14
Q

What is the mnemonic to remember the mechanisms of M1, M2, and M3 receptors?

A

qiq (Kick) in which M1 is Gq, M2 is Gi, and M3 is Gq

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15
Q

What are some muscarinic agonist effects?

A
  1. heart → M2 activation leads to decrease in heart rate, conduction, and force (bradycardia)
  2. exocrine glands → M3 increase in secretion (lachrymal, tracheobronchial, salivary, digestive, sweat glands)
  3. smooth muscles → M3 increase in contraction (while M2 inhibits relaxation)
  4. sphincters → M3 relaxation
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16
Q

What are some CNS effects of muscarinic agonists?

A
  1. not all muscarinic agonists are able to access the CNS (because of the net charge)
  2. CNS effects mainly mediated by M1 receptors
  3. produces tremor, hypothermia, increased locomotor activity, improved cognition
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17
Q

What is the mechanism of acetylcholine neurotransmission?

A
  1. choline is transported into the presynaptic nerve terminal by a Na+ dependent choline transporter (CHT) → the transporter can be inhibited by hemicholinium (no current clinical use)
  2. acetylcholine is synthesized from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT)
  3. acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle associated transporter (VAT) → can be inhibited by vesamicol (no current clinical use)
  4. release of the transmitter occurs when an action potential opens voltage sensitive Ca2+ channels and increases the intracellular calcium → the fusion of vesicles with the surface membrane results in the release of acetylcholine → this step can be clocked by botulinum toxin (botox)
  5. acetylcholine binds to cholinoceptors on the postsynaptic cell
  6. acetylcholine’s action is terminated by metabolism by the enzyme acetylcholinesterase (AChE)
  7. autoreceptors and receptors on the presynaptic nerve ending modulate transmitter release
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18
Q

What are the two classifications of cholinergic agonists?

A
  1. direct acting (muscarinic receptor agonists)

2. indirect acting (potentiating ACh) → aka AChE inhibitors

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19
Q

What are examples of direct acting cholinergic agonists?

A
  1. choline esters → ACh, methacholine, carbachol, bethanechol
  2. alkaloids (natural products) → muscarine, pilocarpine
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20
Q

What are examples of indirect acting cholinergic agonists?

A

reversible → edrophonium, physostigmine, neostigmine

irreversible → organophosphates

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21
Q

What are the symptoms of fast mushroom poisoning?

A

PSNS → bradycardia, nausea, cramps, vomiting, diarrhea, bronchoconstriction, salivation, visual disturbances
SNS → sweating, hypotension (via uninnervated muscarinic receptors in blood vessel endothelium cells mediating vasodilation via NO)

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22
Q

How is the structure of methacholine different than acetylcholine?

A

methacholine has an additional methyl group on the beta carbon (introduces chirality!) → selectively reduces binding with nicotinic receptor and reduces hydrolysis by acetylcholinesterase → mimics (+) muscarine so it increases binding with muscarinic receptor

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23
Q

How is the structure of carbachol different than acetylcholine?

A

carbachol has no acetyl moiety since it is replaced by a carbamate group → makes the molecule less susceptible to esterases

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24
Q

How is the structure of bethanechol different than acetylcholine?

A

bethanechol has the additional methyl group on the beta carbon in addition to the acetyl moiety being replaced by a carbamate group

25
Q

What is the mechanism of direct acting agonists?

A

binds to the receptor directly to exert function

26
Q

What is the difference between muscarinic receptors and nicotinic receptors?

A

muscarinic receptors are stereoselective while nicotinic receptors are not

27
Q

How is the stereochemistry of acetylcholine important?

A

the trans conformation of acetylcholine is the stronger conformation for the muscarinic receptor

28
Q

What is the structural difference between acetylcholine and pilocarpine?

A

pilocarpine has no choline group so the molecule is not charged like acetylcholine → can still bind to muscarinic receptors but has more CNS access

29
Q

What are some uses for pilocarpine?

A
  1. xerostomia (dry mouth, cottonmouth) → pilocarpine is used for the treatment of xerostomia that follows head and neck radiation treatments (M3 receptor)
  2. Sjogren’s syndrome (an autoimmune disorder occurring primarily in women in which secretions from the salivary glands are reduced) → pilocarpine is useful in increasing secretions
30
Q

What are the clinical uses of muscarinic receptor agonists?

A
  1. pilocarpine → open angle glaucoma, dry mouth due to hypofunction of salivary glands (Sjogren’s or cancer radiotherapy → xerostomia)
  2. bethanechol → GI stimulation or treatment of urinary retention
  3. methacholine → provocative test for hyperactive airways
  4. carbachol → ocular (glaucoma, surgery)
31
Q

What are the side effects of muscarinic receptor agonists (depends on particular agonist)?

A
  1. PSNS effects such as DUMBBELS: diarrhea, urination, miosis, bradycardia, bronchoconstriction, emesis, lacrimation, salivation + sweating (SNS effect)
  2. use with caution in patients with asthma, coronary insufficiency, or peptic ulcer
  3. cardiovascular
  4. respiratory
32
Q

Why are antimuscarinic drugs contraindicated in glaucoma?

A

muscarinic agonists like pilocarpine are used to treat glaucoma so antimuscarinic drugs would be contraindicated in glaucoma since it would lead to even more increased intraocular pressure

33
Q

What is the ranking of susceptibility to acetylcholinesterase?

A

acetylcholine → methacholine → carbachol → bethanechol → pilocarpine

34
Q

Which muscarinic agonist has the greatest effect on the cardiovascular system?

A

methacholine → acetylcholine

35
Q

Which muscarinic receptor has the greatest effect on the GI tract?

A

bethanechol and carbachol

36
Q

Which muscarinic receptor has the greatest effect on the bladder?

A

bethanechol and carbachol

37
Q

Which muscarinic receptor has the greatest effect on the eye?

A

pilocarpine

38
Q

Which muscarinic receptor has the greatest effect on sweating?

A

pilocarpine

39
Q

Which muscarinic receptor is more affected by antagonism by atropine?

A

acetylcholine, methacholine, and bethanechol

40
Q

Which muscarinic receptor has the greatest nicotinic effects?

A

carbachol

41
Q

How is glaucoma treated?

A

with muscarinic agonist (pilocarpine) and cholinesterase inhibition

42
Q

How is Sjogrens treated?

A

with muscarinic receptor (pilocarpine)

43
Q

How is GI hypomotility treated?

A

with muscarinic agonist (bethanechol)

44
Q

How is urinary retention treated?

A

with muscarinic agonist (bethanechol)

45
Q

What are nicotinic receptors?

A
  1. respond to acetylcholine and nicotine
  2. ligand gated Na+ channel in which the depolarization leads to the opening of the voltage gated Na+ channels to produce an action potential
  3. less stereoselective than muscarinic receptors
46
Q

Where are nicotinic receptors located?

A
  1. skeletal muscle endplate (Nm)
  2. autonomic ganglia (ANS) (Nn or Ng) → both sympathetic and parasympathetic ganglia
  3. brain (CNS) (Nn)
47
Q

What is the structure of nicotine?

A
  1. is dibasic → has two pKa values

2. at physiological pH, nicotine will most likely be positively charged (protonated)

48
Q

What are the effects of nicotine at low, high, and toxic doses?

A
  1. low doses → stimulate reticular activating system (alerting) and dopamine release (addictive)
  2. high doses → cardiovascular effects (hypertension, tachycardia)
  3. toxic doses → seizures, loss of receptor selectivity leading to bronchorrhea, excessive secretions, and GI disturbance (including nausea and vomiting), neuromuscular blockade
49
Q

What are the acute toxicity effects of nicotine?

A

convulsion, coma, hypertension, arrhythmias, neuromuscular failure

50
Q

What are the bad effects of nicotine?

A
  1. produces tolerance → need more nicotine to produce the same effect
  2. produces physical dependence
51
Q

What are the withdrawal symptoms of nicotine?

A

irritability, anxiety, dysphoria, difficulty concentrating. restlessness, decreased heart rate, increased appetite

52
Q

What counts as successful smoking cessation?

A
  1. reduced craving

2. inhibit reinforcing effects

53
Q

What are prescription and non-prescription nicotine replacement therapies?

A
  1. prescription → Nicotrol inhaler and Nicotrol nasal spray

2. non-prescription → Nicorette gum and Nicoderm/nicotrol transdermal patch

54
Q

What are important things to know about Varenicline (Chantix)?

A
  1. mechanism → alpha4beta2 neuronal nicotinic receptor partial agonist that binds in the CNS to 1) produce low to moderate release of dopamine at reward centers in the brain that mimic nicotine’s effect and reduce withdrawal symptoms 2) blocks the binding of nicotine and is the positive reinforcement gained through smoking
  2. PK → half life is 24 hours and is excreted unchanged in the urine (not really metabolized)
  3. adverse effects → nausea, headache, abnormal dreams, constipation, vomiting
  4. boxed warning → can cause serious neuropsychiatric events like depression and suicidal ideation
  5. structure → charged at physiological pH
55
Q

What is the comparison of varenicline (Chantix) compared to other nicotine replacement therapies?

A

more effective than nicotine patch and gum, and may even be more effective than bupropion

56
Q

Which two cholinergic receptor agonists bind to both muscarinic and nicotinic receptors?

A

acetylcholine and carbachol

57
Q

What are important points about bupropion (Wellbutrin)?

A
  1. action → weakly inhibits NET and DAT resulting in increased levels of norepinephrine and DA in synaptic cleft
  2. clinical use → depression, smoking cessation
  3. problems → delay in effect by a few weeks, lowered seizure threshold (at higher doses), potential for hypertensive crisis with MAOIs
  4. may be less effective for smoking cessation than varenicline
58
Q

What are important things to note about vaping/e-cigarettes (aka electronic nicotine delivery system (ENDS)?

A
  1. common components → nicotine (may be nicotine free), propylene glycol or glycerol as the vapor, flavorings, and others (like metals)
  2. may be effective for some in smoking cessation or reduction
  3. adverse health effects → possible nicotine dependence for new users, severe lung illness (associated with refilled e-cigarette cartridges)
59
Q

How can toxicities arise from liquid nicotine?

A

arise from absorption across mucus membranes in the mouth, absorption from the intestinal tract, absorption through the skin

Therapeutics (15 decks)

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