Lecture 38

Question 1

Cholinergic Blocking Drugs

Answer 1

• 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

Question 2

Natural Mus. Antagonists

Answer 2

• 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

Question 3

Scopolamine

Answer 3

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

Question 4

Atropine

Answer 4

• 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

Question 5

Organophosphate Poisoning + Atropine

Answer 5

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)

Question 6

Atropine v.s. ACh

Answer 6

• 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

Question 7

Atropine Analogs

Answer 7

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

Question 8

Antimus. + Bronchial Asthma

Answer 8

• 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

Question 9

Ipratropium Bromide

Answer 9

• 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

Question 10

Tiotropium Bromide

Answer 10

• 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

Question 11

Synthetic Muscarinic Antagonists

Answer 11

• 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

Question 12

Mus. Antagonist Structure Requirements

Answer 12

• 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

Question 13

Quat. Ammonium Antagonists

Answer 13

• Propantheline chloride

- Pharmacore: ester + amine + aromatic ring

Question 14

Glycopyrrolate

Answer 14

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

Question 15

Tertiary Amine Antagonist

Answer 15

• 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

Question 16

Benadryl

Answer 16

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

Question 17

Amino ether/Amino alcohol analogs

Answer 17

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

Question 18

Selective Mus. Antagonists

Answer 18

• 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

Question 19

SAR- Muscarinic Antagonists

Answer 19

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

Question 20

Acyl Groups

Answer 20

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

Question 21

SAR: Agonists versus Antagonists

Answer 21

• 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

Question 22

Propantheline Chloride

Answer 22

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

Question 23

Physicochemical and PK Parameters

Answer 23

• 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)

Question 24

Metabolism

Answer 24

• 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

Question 25

Fesoferodine

Answer 25

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