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MTP > Exam 3: Cholinergics Part 2 > Flashcards

Exam 3: Cholinergics Part 2 Flashcards

1
Q

What are the 2 types of cholinesterases in humans?

A
  1. Acetylcholinesterase (AChE)
  2. Butyrylcholinestease (BuChE)
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2
Q

Where is AChE located?

A

Associated with glial cells in the synapse

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3
Q

What is the function of AChE?

A

Catalyzes the hydrolysis of ACh (serine hydrolase)

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4
Q

Where is BuChE located?

A

Human plasma (pseudocholinesterase)

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5
Q

What is the function of BuChE?

A

May hydrolyze dietary ester and drug molecules in the blood

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6
Q

What is a the classification of AChEIs?

A

Indirect cholinomimetics that does not involve the binding to cholinergic receptors

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7
Q

How does AChEI prevent the degradation of ACh?

A
  1. Causes increase in the concentration of ACh in the synapse and prolongs the duration of ACh in the junction
  2. Non selective response at both muscarinic and nicotinic receptors
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8
Q

What are the reversible AChE inhibitors?

A

Aryl carbamates

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9
Q

What is the function of aryl carbamates?

A

Agonists like carbachol and bethanechol that are competitive inhibitors of AChE, hydrolyzed more slowly

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10
Q

What is the MOA of reversible AChEI?

A

Transesterifies the Ser residue of ACh with carbamic acid

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11
Q

Compare the rates of acetylated and carbamylated enzymes?

A

A: Rate of regeneration in milliseconds (faster)

C: Rate of regeneration in minutes (slower)

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12
Q

What are the benefits of secondary and tertiary nitrogens for AChE inhibition?

A

Slower metabolism and longer duration of action

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13
Q

What is the rate of this AChE inhibition?

A

Long minutes due to secondary carbamate and aromatic ring

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14
Q

What does this inhibitor achieve?

A
  1. High enzyme affinity but a slow mechanism of action and enzyme regeneration
  2. Reversible AChEI
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15
Q

What is physostigime used for?

A
  1. Myasternia gravis, glaucoma, and urinary retention
  2. Antidote for atropine poisoning
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16
Q

What are metabolites of physostigmine degradation?

A

Eseroline and rubreserine

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17
Q

What are the side effects of physostigmine?

A

Diffuses into the CNS, therefore, large doses causes convulsions (CNS effects)

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18
Q

Describe the similarities of Neostigmine and Pyridostigmine

A
  1. More stable than shysostigime with longer MOA
    1. Effective orally with no CNS activity
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19
Q

What is the therapeutic use for this drug?

A

Neostigmine is AChEI that is used to prevent atony of the intestinal, skeletal, and bladder musculature. Urinary stimulant

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20
Q

What is the therapeutic use for this drug?

A

Pyridostigmine that is widely used AChEI for myasthenia gravis

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21
Q

What is atony?

A

Loss of musclular tone

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22
Q

What is the mechanism of action for irreversible AChEI?

A

Transesterifies the Ser residue of ACh with phosphate esters

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23
Q

Why is phosphate esters more stable than carbamate esters?

A
  1. Phosphorylated enzyme’s rate of regeneration is hours
  2. Phosphoester can undergo aging to prevent hydrolytic regeneration of enzyme even with antidote
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24
Q

What is aging?

A

Cleavage of one or more of the phosphoester bonds while AChE is phosphorylated

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25
Q

What happens to phosphoester once aged?

A

Produces an anionic phosphate rendeering the phosphorous atom much less electrophilic and less likely to undergo hydrolytic cleavage. Irreversible creating a dead enzyme.

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26
Q

What is the deadly phosphorous-derived warfare agent?

A

Sarin

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27
Q

What is 2-pam?

A

The only available and clinically effective antidote for Irreversible AChEI?

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28
Q

Why is 2-pam effective?

A

Oxime moety possess a strongly (super) nucleophilic oxygen atom that undergos self-transesterfication by cleaving the phosphate ester from active site

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29
Q

What are examples of AChEI used to treat Alzheimers?

A
  1. Tacrine (Cognex)
  2. Donepezil (Aricept)
  3. Rivastigime (Exelon)
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30
Q

What are the characteristics of this drug?

A

Tacrine

  1. Nonclassical AChEI
  2. 20% efficacy
  3. Blocks both AChE and BuChe
  4. Has hepatotoxic side-effects
  5. Treats Alzheimers
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31
Q

What are the characteristics of this drug?

A

Donepezil

  1. Selective non-competitive AChEI
  2. 1000x more selective for AChE than BuChE
  3. Greater affinity for AChE in the brain than the periphery
  4. Low hepatotoxicity
  5. Treat Alzheimers
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32
Q

What are the characteristics of this drug?

A

Rivastigmine

  1. Pseudo-irreversible AChEI
  2. Has a half-life of 2 hours (centrally selective aryl carbamate)
  3. Drug action of 100 hours
  4. Low hepatotoxicity
  5. Treats Alzheimers
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33
Q

What types of AChEI used for insectitides?

A
  1. Carbaryl
  2. Malathion
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34
Q

What is the function of this molecule?

A

Carbaryl

  1. Used as insectiside for house plants and vegetables
  2. Used to control flease and ticks on pets
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35
Q

What is the function of this molecule?

A

Malathion

  1. Selectively toxic possesses a dithiophosphate which is converted to phosphate esters by microsomal oxidation in insects
36
Q

Why is malathion non toxic for humans?

A
  1. Not toxic in human because of hydrolysis by plasma esterases to carboxylic acid metabolites
  2. Poor inhibitor of AChE
37
Q

What are muscarinic antagonists?

A

Agents that have high binding affintiy for muscarinic receptor but have no intrisic activity

38
Q

How do muscarinic antagonists differ from agonists?

A

Reversible with no intrinsic activity compared to agonists

39
Q

What are other names for muscarinic antagonists?

A
  1. Anticholinergics
    1. Antimuscarinics
    2. Cholinergic blockers
    3. Antispasmodics
    4. Parasympatholytics
40
Q

Why should muscarinic antagonists not only be called anticholinergics?

A

It implies that the agent is nonselective antagonist to both muscarinic and nicotinic. Muscarinic antagonists is only selective to muscarinic receptors.

41
Q

Where a solanaceous alkaloids found?

A

Henbane, deadly nightshade, jimson weed

42
Q

What is a belladona alkaloid?

A

Esters of tropic acid and either tropine or scopine

43
Q

What examples of solcanaceous alkaloids?

A
  1. Atropine
  2. Methylatropine
  3. Scopolamine
  4. Methschopolamine
44
Q

What molecule is this?

A

Atropine (Solanaceous alkaloids)

45
Q

What are the 2 types of Atropine?

A
  1. (+/-)-Hyoscyamine
  2. (-)-Hyoscyamine
46
Q

What are the medications derived from (+/-)-Hyoscyamine?

A
  1. Tropin
  2. Eumydrin
  3. Atropisol
47
Q

What are the medications derived from (-)-Hyoscyamine?

A
  1. Levsin
  2. Symax
  3. Anaspaz
  4. Cytospaz
48
Q

Why does methylatropine bind better than atropine?

A

Methyl group addition makeing the Nitrogen quaternary and charged, better derivative of ACh for receptors

49
Q

Why is the methylatropine does not have effective bioavailability?

A

Permanent charge hinders it from crossing the BBB compared to atropine

50
Q

What are the marketed medications of scopolamine?

A
  1. Scop
  2. Scopderm
51
Q

What are the marketed medications of methscopolamine?

A

Pamine

52
Q

Compare Scopolamine and methscopolamine

A

S: Treatment of motion sickness, antispasmodic, antiemetic, mydratic, preanasthetic medicant

M: Binds better to receptor but low distribution, used as GI antispasmotic and adjuct treatment to duadenal ulcers

53
Q

Describe the SAR of cholinergic antagonists of listed elements

A
  1. N: tertiary- not as potent as the quaternary but has CNS activity
  2. N: quaternary- present in the most potent antagonist but only has ANS activity not CNS, often bicyclic
  3. X: normally an ester susceptible to chemical breakdown. Can be an ether (more stable) or rarely a carbon
  4. Chain: need at least two carbons long sometimes three
  5. A: usually substituted by 1 phenyl ring
  6. B: usually an aromatic ring, cycloalkyl, or aliphatic unit
  7. C: can be –OH, -CH2OH, -H, or –CONH2
54
Q

What is the therapeutic use for this drug?

A

Dicyclomine

  1. Used in treatment of GI tract spasms, dysmenorrhea, and biliary dysfunction
  2. Decreased side effects compared to atropine like agents
  3. Cholinergic antagonist
55
Q

What is the therapeutic use for this drug?

A

Eucatropine

  1. Used topically in eye examination
  2. Dilation occurs 30 minutes and returns to normal in 2-3 hrs
  3. Cholinergic antagonist
56
Q

What is the therapeutic use for this drug?

A

Isopropamide

  1. Used in the treatment of peptic ulcer and other conditions of the GI tract associated with hypermotility and hyperacidity
  2. Long duration of action, single dose effect can last usp to 12 hrs
  3. Cholinergic antagonist
57
Q

What are the side effects of isopropamide?

A
  1. Dryness of outh, mydriasis, difficulty in urination
  2. Contraindicated in glaucoma
58
Q

How does the SAR reflect the drug’s properties?

A

Glycopyrrolate (Nodapton, Robinal, Tarodyl)

  1. Quaternary carbon with no CNS activity
  2. Ester can undergo hydrolysis (breakdown)
  3. Localized GI breakdown
  4. Easily excreted
  5. Cholinergic antagonist
59
Q

How does the SAR reflect the drug’s properties?

A

Iprotropium (Atem, Atrovent, Narilent)

  1. Oral and inhalation to coat throat and mouth
  2. More localized effect do to ester hydrolysis and charged
  3. No CNS activity due to quaternary N
  4. Hydrophillic
  5. Charged induces low absorption
  6. Cholinergic antagonist
60
Q

How does the SAR reflect the drug’s properties?

A

Procyclidine (Arpicolin, Kemadrin, Osnervan)

  1. Tertiary N provides CNS activity (lack of charge)
  2. Higher C ratio indicating lipophillic to penetrate the BBB
  3. Antiparkinson
  4. Cholinergic antagonist
61
Q

How does the SAR reflect the drug’s properties?

A

Trihexyphenidryl (Aparkane, Artane, Broflex, Tremin)

  1. Tertiary N provides CNS activity (lack of charge)
  2. Higher C ratio indicating lipophillic to penetrate the BBB
  3. Antiparkinson
  4. Cholinergic antagonist
62
Q

How does the SAR reflect the drug’s properties?

A

Tolterodine (Detrol)

  1. Urinary Incontinence
  2. More lipophillic to induce reabsorption
  3. No CNS activity
  4. Cholinergic antagonist
63
Q

How does the SAR reflect the drug’s properties?

A

Benztropine (Congentin, Cogentinol)

  1. Antiparkinson
  2. Lipophilic to penetrate BBB
  3. Tertiary N for CNS activity
  4. Decreased potency compared to 2 C chain
  5. Cholinergic antagonist
64
Q

How does the SAR reflect the drug’s properties?

A

Trospium Chloride (Sanctura)

  1. GI and urinary antispasmodic
  2. Charged N indicating excretion
  3. Cholinergic antagonist
65
Q

How does the SAR reflect the drug’s properties?

A

Orphenadrine (Banflex, Norflex, Flexon)

  1. Ortho group directs use towards muscarinic away from antihistamine
  2. No CNS activity
  3. Muscle relaxant (skeletal)
  4. Slight antihistaminic properties
  5. Cholinergic antagonist
66
Q

How does the SAR reflect the drug’s properties?

A

Tiotropium Bromide (Spiriva)

  1. Selective for M3 due to localized delivery
  2. Thiophen rings are lipophillic instigating long retention time if not metabolized
  3. Cholinergic antagonist
67
Q

What are the physiocochemical properties affecting PK?

A
  1. Agents with quaternary ammonium is not well-absorbed from the GI tract (used to the reduce secretiona and motility in GIT
  2. Agents with tertiary nitrogen is ideal for absortion and distribution. For systemic effects.
  3. Amino ether and amino alcohol-derived agents can cross the BBB (for Parkinson’s and central anticholinergic effects)
68
Q

What makes nicotinic antagonists therapeutically useful?

A

Competive and reversible by ACh

69
Q

What are the subclasses of nicotinic antagonists?

A
  1. Skeletal neuromuscular blocking agents
  2. Ganglionic blocking agents
70
Q

What are the therapeutic application of nicotinic antagonists?

A
  1. Used as general anesthesia for skeletal muscle relaxation
    1. Correction of dislocations and realignment of fractures
    2. Short acting agents used to assist in tracheal intubations
71
Q

What are the side effects of nicotinic antagonists?

A
  1. Hypotension, brochospasm, and cardiac disturbances
  2. Depolarizing agents may cause an initial muscle fasciculation prior to relaxation
  3. Can release histamine followed by subsequent cutaneous, pulmonary, and cardiovascular effects
72
Q

What are the properties of this drug?

A

Tubacurarine (Jexin, Tubarine)

  1. Plant alkaloid isolated from Chondodendron tomentosum
  2. Causes muscle paralysis and has a rapid onset of action
  3. Nicotinic antagonist
73
Q

What are the properties of this drug?

A

Metocurine (Metubine)

  1. Semisynthetic analog of turbocurarine
  2. Product of tubocurarine and methyl iodide reaction
  3. More potent do to addition of methylations on phenol groups and tertiary nitorgen
  4. Nicotinic antagonist
74
Q

What are the properties of this drug?

A

Decamethonium (Syncurine)

  1. First agents to be synthesized
  2. Nitrogens is separated by 10-12 carbon atoms for optimal blocking activity
  3. Acitivity diminishes by the increase or decreases of carbons
  4. Nicotinic antagonist
75
Q

What is hexamethonium?

A

Compound with 6 carbons used as an nicotinic antagonists at autonomic ganglia (Blocking agent as an antihypertensive agents)

76
Q

What are this drug’s properties?

A

Succinylcholine (Anectine)

  1. 2 molecules of acetylcholine connected susceptibel to hydrolysis
  2. Nicotinic antagonist
77
Q

What is the purpose for steroid based agents?

A

Desinged for neuromuscular blocking agents that is nonpolarizing and inactivated by metabolism

78
Q

What are the common steroid-based agents?

A
  1. Pancuronium
  2. Vecuronium
  3. Pipecuronium
  4. Rocuronium
79
Q

What are the pros and cons of steroid-based agents?

A

Effective as neuromuscular blocking, but depolarization it a problem for agents containing bis-quaternary functionality

80
Q

What are properties of this drug?

A

Pancuronium (Mioblock, Pavulon)

  1. Long action DOA and more potent than tubocurarine
  2. Increases BP and HR
  3. Metabolized in liver by hydrolysis and excreted in urine due to permanent ionization
  4. Steroid-based agent
81
Q

What are the properties of this drug?

A

Vecuronium (Musculax, Norcuron)

  1. Intermediate acting agent with no histamine release
  2. No cardiovascular effects at therapeutic doses
  3. Metabolized in liver and excreted in the urine from ionization
  4. Steroid-based agent
82
Q

What are the properties of this drug?

A

Pipecurium (Arduan)

  1. Long DOA with minimal cadiovascular effects
  2. Excreted mostly unchanged in urine
  3. Caution for patients with decreased renal function
  4. Steroid-based agent
83
Q

What are the properties of this drug?

A

Rocuronium (Esmeron, Zemuron)

  1. Intermediate acting agent with DOA like Vecuronium but more rapid onset
  2. No histamine release
  3. Steroid-based agent
84
Q

What are examples of tethahydroisoquinoline-based agents?

A
  1. Atracurium (Tracrium)
  2. Mivacurioum (Mivacron)
  3. Doxacurium (Nuromax)
85
Q

What are the properties of this drug?

A

Atracurium (Tracrium)

  1. Tethahydroisoquinoline-based agents
  2. Non-depolarizing agent on each quaternary ammonia
  3. DOA is slightly longer than succinylcholine
  4. Undergos ester hydrolysis and Hoffman in the liver
86
Q

What are the properties of this drug?

A

Mivacurium (Mivacron)

  1. Short acting DOA from plasma cholinestarse hydrolysis
  2. Tethahydroisoquinoline-based agents
87
Q

What are the properties of this drug?

A
  1. Tethahydroisoquinoline-based agents
  2. Longest DOAs of all the neuromuscular blocking agents and minimally metabolized
  3. Excreted unchanged by the kidney so no Hoffman elimination

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