Synthesis:

- from l-histadine by histidine decarboxylase

Storage:

- found in most tissue but esp lungs, skin, and GIT

- intracellular granules of mast cells and basophils

- bound form inactive

Release:

- immunological (IgE or other inflammatory mediator)

- chemically (e.g. morphine)

H1 has Gq

H2 has Gs

H3 has Gi/Go

H4 has Gi

H1 receptors

- G-protein

- Tissue distribution

- End products/result

G-protein =  Gq

Tissues:

- smooth muscle

- endothelium

- brain (postsynaptic)

End products:

- NO

- cAMP

- cGMP

- PLA₂

- PLD

H2 receptors

- G-protein

- Tissue distribution

- End products/results

G-protein = Gs

Tissue:

- gastric mucosa

- heart

- mast cells

- brain (postsynaptic)

End product:

- increased cAMP

H3 receptor

- G-protein

- Tissue distribution

- End product/result

G-protein = Gi/Go

Tissue:

- mostly neural

End result:

- decreased neurotransmitter release

H4 receptor

- G-protein

- Tissue distribution

- End products/result

G-protein = Gi

Tissue:

- bone marrow

- white blood cells

End result:

- eosinophil and mast cell chemotaxis

H1 receptors:

- stimulate sensory nerve endings (urticaria)

- depolarize afferent nerve endings

- modulate respiratory neurons signaling inspiration/expiration

H3 receptors:

- reduce the release of ACh, amine, and peptide transmitters

Decreases Systolic and Diastolic BP via arteriolar dilation:

- release of endothelial NO (low doses; H1 receptor)

- cAMP (large doses; H2 receptors)

Increases HR:

- reflex tachycardia (low dose)

- direct stimulation of cardiac H2 receptors (high dose)

Increases ventricular contraction via H2 receptors

Decreases atrial contractility via H1 receptors

Increases capillary permeabilty via H1 receptors

Triple response: reddening of skin, wheal, flare

Increases gastric acid secretion via H2 receptors

Decreases gastric acid secretion via H3 receptors

Constricts intestinal smooth muscle via H1 receptors

First Generation Anti-histamines

- General info

• lipid soluble
• antagonize action of histamines via H1 receptors
• little value in allergic bronchospasm
• some effects - blockade of 5-HT, α or muscarinic receptors
• side effects are sometimes desireable e.g. sedation
• most common side effects
• anti-cholinergic, sedative, GI
• well absorbed after oral administration

- sedation

- anti-parkinsonism

- anti-cholinoceptor

- anti-alpha adrenergic

- anti-serotoninergic

- local anesthetic

Actions:

- strong sedative

- strong anti-cholinergic

- anti-motion sickness

Actions:

- mild anti-cholinergic

- moderate sedative

- GI side effects

Hydroxyzine

Cyclizine

Actions:

- strong sedative and anxiolytic

- mild sedative and anti-motion sickness respectively

Brompheniramine

Chorpheniramine

Actions:

- mild anti-cholinergic

- mild sedative

- In OTC cold preparations

Actions:

- strong sedative

- strong anti-cholinergic

- anti-emetic

Actions:

- moderate sedative

- mild anti-cholinergic

- anti-serotonergic

• less lipid soluble
• less sedative than 1Gs
• less likely to block autonomic receptors than 1G
• longer acting than 1G
• metabolized by CYP3A4 system

2nd Generation Drugs

- Drug(s)

- Dosing hours

- Actions

Drugs:

- Loratadine (Claratin)

- Cetirizine (Zyrtec)

- Fexofenadine (Allegra)

Dosing hours:

- 24

Uses:

- Allergies

Not yet in use

H3 blockers

- sleep disorders

- obesity

- cognitive and psychiatric disorders

H4 blockers

- anti-inflammatory (asthma)

Serotonin Receptors- General Info

- How many types

- 2nd messenger systems and exception

7 subtypes of serotonin receptors

5-HT₃ is a nicotinic/GABA_A family Na/K channel the rest are G-protein coupled receptors

Nervous system actions of Serotonin

- Neurotransmitter

- precursor to melatonin in pineal gland

- 5-HT₃ in medulla and GIT - vomiting  reflex

- 5-HT_1P and 5-HT₄ enteric nervous system

- sensory nerve 5-HT₃ - pain, itching

Constricts bronchial smooth muscle - 5-HT_2A

Facilitates release of ACh from vagus nerve

-constricts most vessel (smooth muscle 5-HT₂) except...

- dilates skeletal and coronary vessels via endothelial 5-HT₂ (NO)

- reflex bradycardia: Bezold-Jarisch reflex (5-HT3)

- triphasic response to IV 5-HT:

   1. decreased HR, BP, CO (Bezold- Jarisch)

   2. BP increases b/c of vasoconstriction

   3. BP decreases b/c of skeletal vessel dilation

- stimulates platelet aggregation (5-HT₂)

- increases tone and facilitates peristalsis

    ~constricts intestinal smooth muscle (5-HT₂)

    ~stimulates enteric ganglionic 5-HT₄ to release ACh

- 5-HT overproduction in carcinoid syndrome = diarrhea

Cyproheptadine

-receptor

-use

Serotonin antagonist

- 5-HT_2A, muscarinic and H₁ antagonist

- for:

   ~carcinoid syndrome

   ~cold-induced urticaria

   ~5-HT syndrome

Clozapine

 Serotonin antagonist

- 5-HT₇ and dopamine receptor antagonist

- atypical antipsychotic with few extrapyramidal side effects

- used in schizophrenia

Ketanserin & Ritanserin:

 Serotonin antagonist

- 5-HT_2A selective antagonist 

- Ketanserin blocks α- adrenergic receptors

- blocks vascular smooth muscle contractions

- platelet aggregation

- approved in Europe for htn tx but not US

Buspirone

-receptor

-function

 Serotonin agonist

5-HT_1A - anxiolytic

Serotonin agonist

(5-HT_1A/1D) - migranes