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Integrated Drug Structure, Function, and Therapeutics Winter Term > Histamine H1 Antagonists - Proteau > Flashcards

Histamine H1 Antagonists - Proteau Flashcards

1
Q

What form do 97% of histamine take at pH 7.4?

A

The monoprotonated form (one in the ring)

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2
Q

What is histamine formed from and how is it metabolized?

A

It is formed from histidine by a decarboxylase. Histamine is metabolized by MAO and diamine oxidase, or by histamine-N-methyltransferase. The methyltransferase adds a methyl group to the N that is protonated.

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3
Q

How many types of histamine receptors are there? What do they each do?

A

4.
H1 mediates bronchoconstriction, small blood vessel constriction, itching in the epidermis, and sleep
H2 is involved in the regulation of gastric secretions
(H3 is located in gastric mucosa and CNS
H4 are immune cell function modulators) not as important

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4
Q

Where is most histamine found?

A

In mast cells

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5
Q

What makes histamine different than other neurotransmitters?

A

It is an autocoid, which means that it is a locally acting hormone that acts near the site of synthesis and release.

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6
Q

What are H1 antagonists generally referred to as?

A

Antihistamines

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7
Q

What can you get scombroid fish poisoning from?

A

Tuna or mackerel. Bacteria is present on these fish and after they die, histidine is released.

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8
Q

What does stinging nettle (or Utica dioca) have on it?

A

Histamine ( and more!)

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9
Q

What is the general SAR for H1 antagonists? (Similar to muscarinic antagonists)

A

X group ( CH-O, N, CH, or CH-N) centrally
Chain of 2 or 3 “CH2” ‘s
A tri-substituted amine, usually dimethyl (test. not quat)
Two aromatic rings attached to the X group, separate or joined.

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10
Q

Diphenhydramine

  • SE’s
  • Antimuscarinic SE’s?
  • Central effects?
A

SE’s: sedation from H1 receptors
Antimuscarinic SE’s
Good central effects, gets into CNS
Amino alkyl ether

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11
Q

What differences do the salt form of diphenhydramine have?

A

Dimenhydrinate

  • 8-chlorotheophylline component is a stimulant (less drowsy-causing)
  • Is used for motion sickness
  • Salt form not brought into CNS
  • Amino alkyl ether
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12
Q

What contributes to Clemastine’s potency?

A

The isomers, particularly the first chiral center.

It is an amino alkyl ether (not relevant)

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13
Q

What isomers are used in Clemastine?

A

Only the R,R isomer (7x more potent than R,S)

R,S is 20-40x more potent than S,S or S,R.

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14
Q

Pyrilamine

  • SE’s
  • Antimuscarinic SE’s?
A

Sedative SE’s

Reduced antimuscarinic SEs compared to amino alkyl ethers

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15
Q

Pheniramine

  • Sedating?
  • X group?
  • R group variations?
  • How does the potency change as the R groups change?
  • Active isomer?
A
  • Least sedating of the first generation antihistamines
  • Ch is X group
  • R group variations: R=H pheniramine. R=Cl chlorpheniramine. R=Br brompheniramine
  • Cl and Br have 10x the potency of pheniramine.
  • S dextro isomer is active
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16
Q

What drug has the black box warning for potentially fatal respiratory depression in patients younger than 2 years?

A

promethazine

17
Q

Promethazine

  • x group
  • ring structure (how is it different than antipsychotics?)
  • use
  • antimuscarinic effects?
A
  • x group is N
  • tricyclic - only 2 carbon bridge over antipsychotic’s, which have 1 3 carbon bridge. So no antipsychotic effects
  • anti-emetic
  • significant anti-muscarinic effects
18
Q

Meclizine

  • X group
  • use
  • anti-muscarinic effects
A
  • x group is CH-N
  • anti-emetic for motion sickness
  • Low affinity for M1 because of piperazine ring benzene ring modification
19
Q

Hydroxyzine

  • TYPE
  • uses
  • anti-muscarinic effects?
  • forms and differences
A
  • piperazine ring w/ polar group
  • used systemically to treat hives. Also tranquilizer. Strong central effects
  • Limited M1 antagonism because of polar group
  • Pamoate (not as water soluble) and HCl. Therapeutically the same, strengths are different.
20
Q

How is hydroxyzine metabolized, and to what?

A

Via a P450 enzyme to cetirizine.

21
Q

Cetirizine

  • difference between cetirizine and hydroxyzine
  • SE’s
  • isomer(s) used
  • CNS access
  • Metabolism
A
  • Carboxylic acid instead of hydroxyl group
  • Greatly reduce sedative effects
  • racemic mixture for ceterizine, R-levocetirizine is active enantiomer and in Xyzal. “Lazy X”
  • Zwitterionic characteristics and P-glycoprotein substrate status limit CNS access.
  • Minimal metabolism, t1/2 = 8 hours
22
Q

Fexofenadine

  • Generation
  • sedating?
  • CNS access?
  • metabolism?
  • absorption?
  • Counseling point for taking?
A
  • 2nd generation
  • zwitterionic character limits CNS access (less sedation), also P-glycoprotein substrate
  • Minimal metabolism, t1/2 = 14 hours
  • Absorption is mediated by OATP (organic anion transporter). Transport is inhibited by grapefruit, orange, and apple juice.
  • Take with water
23
Q

Loratadine

  • structure
  • metabolism
  • Generation
A
  • No basic nitrogen, tricyclic system, has carbamate
  • o-dealkylation to carbonic acid, which is unstable. CYP 3A4 and 2D6 used. (oxidative elimination of carbamate rather than hydrolysis).
  • 2nd generation, not drowsy-causing.
24
Q

Desloratadine

  • structure
  • H1 affinity
  • CNS access
  • Metabolism
A
  • Secondary amine, lipophilic structure (seems to have CNS access)
  • Greater affinity for the H1 receptors than loratadine
  • lipophilic structure says yes CNS, but P-glycoprotein substrate status says stay out!
  • t 1/2 = 27 hours to active metabolite
25
Q

Ketotifen

  • dual action as what?
  • structure?
  • type
A
  • blocks action of histamine at receptor, and acts as a mast cell stabilizer to prevent the release of histamine.
  • ketone with tertiary amine
  • H1 antagonist, mast cell stabilizer. Structurally similar to loratadine.
26
Q

Alcaftadine

  • structural features
  • metabolism
A
  • Aldehyde (better absorption than carboxylate, but then oxidized to active carboxylate, which is zwitterionic and reduces CNS access)
  • Oxidation to active carboxylate, which gives the bulk of the antagonist action.
27
Q

Olopatadine

  • Structure
  • Derivative of?
  • Characteristics
  • Action?
A
  • Tricyclic ring system with aldehyde and carboxylic acid
  • derivative of doxepin
  • zwitterionic character (limited CNS access)
  • Mast cell stabilizer, H1 antagonist
28
Q

Azelastine

  • Action
  • Structure
A
  • Mast cell stabilizer and H1 antagonist

- Used as a racemate, both enantiomers are equally effective (structural variant)

Integrated Drug Structure, Function, and Therapeutics Winter Term (18 decks)

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