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811 > Lecture 38 > Flashcards

Lecture 38 Flashcards

Muscarinic Antagonists - Feng

1
Q

Cholinergic Blocking Drugs

A
  • Used in conditions that require reduced cholinergic stimulation
  • Bind to ChR but have little to no effect, prevents binding of cholinergic agonists
  • Two major categories: Muscarinic and Nicotinic Antagonists
  • High affinity for ChR and decreased numbers of free receptors
  • Similar to ACh but with additional substituents that enhance their binding to ChR
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2
Q

Natural Mus. Antagonists

A
  • Tertiary amine, alkaloid, ester of tropic acid: atropine or scopolamine
  • Can cross BBB as free bases
  • Become protonated and antagonize mus. receptors
  • CNS effects at high doses include hallucinations
  • In atropine, also see restlessness, agitation, and hyperactivity
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3
Q

Scopolamine

A
  • Epoxy group
  • Source - thorn apple
  • Used to treat motion sickness
  • More CNS effects (including amnesia) than atropine due to increased lipid solubility
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4
Q

Atropine

A
  • Racemic form of hyoscyamine
  • Source - roots of belladonna (deadly nightshade)
  • Similar affinity for various mus. receptor subtypes
  • Used medically to decrease GI motility, dilate pupils, and as a AntiChE poisoning antidote
  • L- is the main effects and D- is weakly active, so combined the mixture is intermediately active
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5
Q

Organophosphate Poisoning + Atropine

A
  1. ACh released from terminal
  2. ACh crosses synaptic cleft and binds with receptor
  3. Nerve agents block AChE ability to stop ACh action
  4. Atropine blocks the receptor so ACh can’t work, no direct affect on nerve agent or AChE (counteracts chol. excess instead)
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6
Q

Atropine v.s. ACh

A
  • Similarities - charged nitrogen and ester group
  • Differences - Aromatic ring = extra binding group (hallmark)
  • Atropine is bigger than ACh, so can bind regions not usually interacting with by ACh, so induced fit doesn’t occur and therefore neither does activation
  • Differ from Scopolamine by not having epoxide in positions 6 & 7
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7
Q

Atropine Analogs

A
  • Ipratropium (1986) and Atropine Methonitrate
  • Ipratropium - bronchodilator and antiasthamtic
  • Atropine methonitrate - decreases GI motility
  • Quat. salts made to decrease CNS effects of Atropine
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8
Q

Antimus. + Bronchial Asthma

A
  • Ipratropiun Bromide and Tiotropium Bromide
  • M3 receptors - cause bronchiole constriction
  • Therapeutic use - block M3 receptor bronchoconstriction and allow for adrenergic bronchiole dilation to help overcome pulmonary constriction of asthma attacks
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9
Q

Ipratropium Bromide

A
  • Atrovent
  • N-isopropyl analog of Atropine
  • Highly hydrophilic and poor absorption from lungs
  • Local, site specific with little systemic circulation
  • Indication: bronchospasm relief with COPD
  • Duration: 4 hours
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10
Q

Tiotropium Bromide

A
  • Spiriva
  • Dithienyl derrivative of N-Methyl scopolamine
  • Indication: bronchospasm relief with COPD
  • Site specific, local medication
  • Longer duration than ipratropium (24 hours)
  • Metabolized by CYP3A4 and CYP2D6, then undergoes glutathione conjugation to form various metabolites
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11
Q

Synthetic Muscarinic Antagonists

A
  • Atropine is the prototype that stands as the basis for other derivatives. Derivatives aim to:
    1. Overcome CNS effects
    2. Archieve selectivity of Mus. receptor subtypes
    3. Specific drug administration
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12
Q

Mus. Antagonist Structure Requirements

A
  • R1 = usually second aryl group or carbocyclic group
  • R2 - usually tertiary hydroxyl or hydroxymethyl group, increase potency by hydrogen bonding with receptor
  • X - ester or ether in most drugs
  • Cationic amine (tertiary or quat.) with small alkyl substituents
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13
Q

Quat. Ammonium Antagonists

A
  • Propantheline chloride

- Pharmacore: ester + amine + aromatic ring

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14
Q

Glycopyrrolate

A
  • Mus. anticholinergic group
  • Synthetic quat. amine, no CNS effects, doesn’t cross BBB
  • Approved in 2018 by FDA to treat excessive underarm sweat
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15
Q

Tertiary Amine Antagonist

A
  • Benztropine (1954) and Oxyphencyclimine (1958)
  • Better absorbed and distributed by all routes of admin.
  • Useful for systemic delivery
  • Useful in CNS disorders: Bentropine is used for Parkinsons
  • Pharmacore: ester + amine + aromatic ring
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16
Q

Benadryl

A
  • Antihistamine
  • SE: fatigue, sedation, and dizziness
  • Fits relatively well to be antichol. agent, can penetrate BBB due to relative lipophilicity
17
Q

Amino ether/Amino alcohol analogs

A
  • Procyclidine - 1955, amino alcohol, no ester/ether
  • Orphenadine - 1959, amino ether, centrally acting muscle relaxant
  • Pharmacore - Oxygen group + amine + aromatic ring
18
Q

Selective Mus. Antagonists

A
  • Most mus. antagonists are also nicotine receptor antagonists at high doses
  • No selectivity for M1 and M2 subtypes usually
  • Pirenzepine - high affinity for M1, GI ulcer, 1 huge ring group
  • AFDX 116 - Cardiac M2 binding, branching of ring is important
19
Q

SAR- Muscarinic Antagonists

A
  1. Tertiary or quat. nitrogen (ionized)
  2. Ester - preferred
  3. N-alkyl groups can be larger than methyl
  4. Large branched acyl groups - aromatic or large rings with important branching groups
20
Q

Acyl Groups

A
  • Must be bulky and arranged specifically
  • Must have hydrophobic regions near normal ACh binding site
  • Needs to be T or Y shaped
21
Q

SAR: Agonists versus Antagonists

A
  • Alkyl groups can be larger than methyls
  • N can be tertiary OR quat.
  • Very large acyl groups allowed, this point is MOST crucial to determining if compound will be an antagonist or not
  • Not as strict as agonist group since it just needs to bind with receptor, doesn’t need to elicit a reaction
22
Q

Propantheline Chloride

A
  • ACh skeleton with hydrophobic acyl side, binds more strongly than ACh itself
  • Extra binding - no response induced
  • Antagonist binding means ACh can’t bind
23
Q

Physicochemical and PK Parameters

A
  • Antichol. are effective orally and parenterally
  • Quat ammonium are not well absorbed, local effects, many available has inhalants for asthma
  • Tertiary N cross BBB and absorbed orally or transdermally (Scopolamine)
24
Q

Metabolism

A
  • Most ester-containing antichol. are susceptible to hydrolysis to inactivated products
  • Toviaz is an exception, activated by hydrolysis
  • N-dealkylation also common reaction resulting in activation
  • Dose adjustments required when given with drugs that increase or decrease CYP-catalyzed reactions
25
Q

Fesoferodine

A
  • Toviaz
  • M3-selective drug for overactive bladder
  • Prodrug, activated by plasma esterases into active metabolite, desfesoterodine

811 (38 decks)

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