Lothstein - Anti-Histamines

Question 1

What are the sites of histamine sythesis?

Answer 1

• L-histidine -> histamine
• Mast cells and basophils have ability to store large amts of histamine (in granules) for its release, when needed
• Control of release in many other cells, but only at the level of conversion of histidine to histamine:
  1. Epidermal cells, intestinal mucosa, CNS neurons, rapidly-dividing cells

Question 2

What are the 4 primary functional sites of histamine?

Answer 2

• Stomach: stimulate production of HCl
• Brain: neurotransmitter -> regulates sleep, hormonal secretion, memory formation, brain arousal (absence of histamine in brain can make you sleepy)
• Immune system: acts as vasodilator in allergies/immune system response
• Role in vasculature and smooth mm focus of the lecture

Question 3

Briefly describe the importance of the histamine receptors.

Answer 3

• Histamine, by itself, has no function -> it has to bind to a receptor
• H1 was the first to be identified
• Roles of histamine can be segregated by the type of receptor it is interacting with (see attached):
  1. H3 believed to control release of histamine from a number of cells
  2. H1/2 also involved in CNS
  3. Focus on H1 antagonists -> no FDA approved drugs out for H3-H4 antagonism yet (H2 antagonists used for GI biz)

Question 4

What are the functions of the different histamine receptors?

Answer 4

• Distinct and overlapping functions
• All 4 receptors can be linked to a variety of nasal symptoms in rhinitis and allergies -> H1 is most important in this regard

Question 5

How can one ligand target multiple receptors?

Answer 5

• Molecules in the body have a complex topology that can often be recognized by different types of receptors
• Histamine can bind 4 different histamine receptors, and other receptors as well -> basis of AE’s and side effects

Question 6

How is histamine release by mast cells controlled?

Answer 6

• Latticework of (-) charged carbs bound to the (+) charged histamine (and other pro-inflammatory cytokines, i.e., LT’s)
• Histamine has a short half-life (prevents systemic effect) -> time-release capsule whereby sodium exchanges with histamine, which is is gradually released
  1. Allows a broader release area of histamine in the body, producing a local-regional effect, rather than an extremely local effect
• Mast cell not destroyed by release -> granules fuse w/PM and release their contents
  1. Takes several days for mast cells to regenerate their supply of histamine

Question 7

Describe the effects of histamine on the vasculature.

Answer 7

• Histamine only has effect where there are histamine receptors -> none in the true capillary bed (permeability actually in the VENULES/ARTERIOLES: VASODILATION)
• H1 (aa and vv): constriction of vessel via smooth mm, but dilation at endothelial level -> net effect on LG VESSELS is VASOCONSTRICTION (smooth mm effect predominates)
  1. This is true in vasculature, and also bronchi (net effect in the lungs is BRONCHOCONSTRICTION)
• H2: slower onset, and more persistent VASODILATION in SM VESSELS -> allows immune system components to move into tissue and confront and destroy allergens (at consequence of itching, sneezing, and runny nose)

Question 8

What happens when a mast cell responds to an allergen?

Answer 8

• Mast cells sensitized by IgE, so when an allergen binds, there is a cross-linking of IgE bound to specific receptors, leading to activation of mast cell and histamine release
• Other substances involved/released from mast cells: LT’s, PG’s, tryptase (but about 1,000,000x more histamine)
• Histamine mostly involved in the early phase allergic response (sneezing, itching, runny nose/rhinorrhea, nasal obstruction -> fluid, swelling due to edema)
  1. This stage is the target of anti-histamines
• Late response: runny nose, watery eyes

Question 9

How do anti-histamine drugs work?

Answer 9

• Unclear, but the proposed mechanism is inverse agonism
• Receptors exist in active and inactive conformation, and activity depends on % of receptors in e/conformation
• Histamine stabilizes the # of receptors in the active conformation
  1. All H1 antagonists can bind the inactive form, and accumulate this conformation, decreasing histamine receptor activity
• Technical difference pharmacologically, but the same effect clinically as competitive inhibition

Question 10

What is the general H1 antagonist structure?

Answer 10

Substitutions on these 3 sites for the drugs

Question 11

What are the therapeutic applications of H1 antagonists?

Answer 11

• Amelioration of allergy and hay fever symptoms
• Treatment of symptoms of insect bites and stings
• Treatment of symptoms of contact flora poisoning
• Attenuation of motion sickness and vertigo (1st gen -> NOT through interaction with histamine receptors, but rather via anti-cholinergic effects)

Question 12

Compare and contrast the 1st and 2nd gen anti-histamines (table).

Answer 12

• 1st gen: 4-6 hour duration, so pt compliance can be a limiting factor
  1. Anticholinergic effects can be beneficial or AE’s.
• 2nd gen: upwards of 24 hour duration

Question 13

What are the properties of the 1st gen H1 antagonists?

Answer 13

• Common functional effects: can almost ignore structural categories; some variations in sedation, but all are sedative
• Sedative effect: H1 receptors in hypothalamus; histamine is a potent regulator of wakefulness and sedation in the brain -> presence of histamine makes you more alert
  1. Drugs pass through BBB (uncharged) -> can bypass P-gp’s, and easily penetrate brain/have CNS effects
• Anti-cholinergic: no such thing as a truly specific agonist or antagonist -> as you INC dose, drug will be able to bind o/receptors, in this case, muscarinic
  1. GI effect is in H2 receptor domain (smooth muscle peristalsis -> mild effect of 1st generation meds)
  2. Contraindicated for the tx of asthma bc dry and thicken mucosal secretions (anti-cholinergic)
• No effect on histamine release from mast cells

Question 14

What are the names and indications of the ether/ethanolamine derivatives?

Answer 14

• Diphenhydramine and Dimenhydrinate: allergic rhinitis, anaphylaxis
  1. Adjunct, common cold, insomnia, motion sickness
  2. Highly sedating
• Clemastine: allergic rhinitis, cutaneous hypersensitivity, uticaria, and angioedema
  1. Highly sedating
• 1st gen: CONTRAINDICATED IN ASTHMA PATIENTS

Question 15

What are the names and indications of the alkylamine derivatives?

Answer 15

• Chlorpheniramine: allergic rhinitis, common cold
• Brompheniramine: allergic rhinitis, urticaria
• 1st gen: CONTRAINDICATED IN ASTHMA PATIENTS

Question 16

What are the indications for promethazine? Derivative of?

Answer 16

• Promethazine: allergic condition, motion sickness, nausea and vomiting
  1. Highly sedating
• Phenothiazine derivative
• 1st gen: CONTRAINDICATED IN ASTHMA PTS

Question 17

What are the names and indications of the piperazine derivatives?

Answer 17

• Cyclizine: motion sickness, nausea and vomiting
• Meclizine: motion sickness, vertigo
• Hydrxoxyzine: nausea and vomiting, pruritis
• 1st gen: CONTRAINDICATED IN ASTHMA PTS

Question 18

Which anti-histamines are contraindicated in asthma patients?

Answer 18

• 1st gen
• Diphenhydramine, Dimenhydrinate, and Clemastine
• Chlorpheniramine and Brompheniramine
• Promethazine
• Cyclizine, Meclizine, and Hydrxoxyzine

Question 19

What are the AE/side effects of the 1st H1 antagonists?

Answer 19

• 1st-generation antagonists are not only targeting the H1 receptor, but can bind, to a lesser extent, other receptors
• Motion sickness treatment is a consequence of muscarinic effects (not H1)
  1. CN VIII -> inner ear and vomit reflex -> block muscarinic transmission through this N
• Also have sedative effect

Question 20

What are the properties of the 2nd gen H1 antagonists?

Answer 20

• Don’t cross BBB nearly as much as 1st gen (bc charged): 70% 1st gen to 20% 2nd gen -> limited to no sedation
• All have the same effect
• Comparable potency to 1st gen for H1 receptor blocking, but NO sedative or anti-cholinergic effect
  1. Little effect on smooth mm peristalsis in the GI tract
• NO effect on bronchial secretions, so can be taken safely by asthma patients (but not first-line asthma drugs).
• Single dose over 24 hours due to pharmacokinetics; un-metabolized (or metabolized to another active form) by liver and secreted in feces or urine
• Note: 2 no longer on market due to interaction with anti-fungals/macrolides leading to fatal cardiac arrhythmias (K channel binding) -> always think about drug combos
  1. Short hx of FDA warnings for use of 2nd gen anti-histamines, but most were IV abuse drugs -> no drug is absolutely safe bc every individual has potential to be different in terms of their response to a drug

Question 21

What are the indications for Loratadine, Fexofenadine, Desloratadine, Acrivastine, and Cetirizine?

Answer 21

Urticaria, seasonal allergic rhinitis

2nd/3rd gen H1 antagonists

Non-sedating

Question 22

What are the indications for Olopatadine, Levocabastine, and Azelastine?

Answer 22

Allergic conjunctivitis, seasonal allergic rhinitis

2nd/3rd gen H1 antagonists

Non-sedating

Question 23

What are the side effects of the 1st gen vs. 2nd gen H1 antagonists?

Answer 23

• 1st gen: sedation, impaired cognition, DEC alertness, slowed rxn time, confusion, dizziness, dystonia, potentiation of nasal congestion
• 2nd gen: mild cognitive disturbance

Question 24

What are the goals of 3rd gen H1 antagonist drug development?

Answer 24

Question 25

Desloratidine (Clarinex)

Answer 25

- _Greater H1 specificty_: 14 to 17x greater binding to H1 receptors than Loratadine - 15 to 50x _lower affinity for muscarinic receptors_ (M1, 2, 4, and 5) compared to H1-receptors - Relatively _long elimination half-life_ (27 hours) - Not going to blow others off market, but is competitive - _Non-sedating, 3rd gen H1 receptor antagonist_ (reverse agonist) 1. Indicated for urticaria, seasonal allergic rhinitis

Question 26

What are the clinical uses of the H1 antagonists, 1st gen vs. 2nd/3rd?

Answer 26

- Note: role of cholinergic receptors in itching dermatosis, so first generation have more of an effect

Question 27

Olopatadine

Answer 27

- Selectivity for H1 receptor \> other ocular antihistamines - _Inhibits release of histamine from mast cells_ 1. May block activities of some additional mediators of ophthalmic inflammation by INH release of tryptase and prostaglandin D2 from same granules - Prevents or _reduces ocular inflammation_ rxns induced by a variety of common allergens 1. Used to treat ocular rhinitis, allergic conjunctivitis, seasonal allergic rhinitis - _Non-sedating, 3rd gen H1 receptor antagonist_ (reverse agonist)

Question 28

Levocabastine

Answer 28

- Rapid-acting agent for as needed-use against _nasal and ocular effects of rhinitis_ - Piperidine derivative: 1250 times more potent than chlorpheniramine - 40,000x effective dose exhibits no other pharmacological effects -\> _perhaps most specific H1 antagonist developed_ so far - _Indications_: allergic conjunctivitis, seasonal allergic rhinitis - _Non-sedating, 3rd gen H1 receptor antagonist_ (reverse agonist)

Question 29

Azelastine

Answer 29

- Phthalazinone derivative that INH histamine + LT activity - _Blocks Ca mobilization and the 5-lipoxygenase pathway_ - INH PAF (platelet activating factor) through receptor antagonism 1. PAF and LT’s are principal mediators of asthmatic attacks, so blocking these actions was hoped to help with asthmatic attacks, but _none of these drugs have been approved primarily for the tx of asthma_ 2. **Anti-histamines that are safe for asthmatics to take, and may be used as adjunctive therapy** - _Indications_: allergic conjunctivitis, seasonal allergic rhinitis - _Non-sedating, 3rd gen H1 receptor antagonist_ (reverse agonist) - Emedastine, Mizolastine, and Ebastine all similar