Histamine

Histamine

• Bioactive amine synthesized from histidine

• Released to produce local effects (centrally and peripherally)

• Role:

  • 1) Immediate Allergic Response → main focus

  • 2) Regulation of basal acid secretion in the stomach

  • 3) Neurotransmitter and modulator of neurotransmitter release

Classification of hypersensitivity Rxn

Immune Reaction	Mechanism	Clinical Manifestations	Timing of Reactions
Type I (IgE-mediated)	Drug-IgE complex binding to mast cells with release of histamine, inflammatory mediators	Urticaria, angioedema, bronchospasms, pruritus, vomiting, diarrhea, anaphylaxis	Minutes to hours after drug exposure
Type II (cytotoxic)	Specific IgG or IgM antibodies directed at drug-hapten coated cells	Hemolytic anemia, neutropenia, thrombocytopenia	Variable
Type III (immune complex)	Tissue deposition of drug-antibody complexes with complement activation and inflammation	Serum sickness, fever, rash, arthralgias, lymphadenopathy, urticaria, glomerulonephritis	1-3 weeks after drug exposure
Type IV (delayed, cell-mediated)	MHC presentation of drug molecules to T cells with cytokine and inflammatory mediator release	Allergic contact dermatitis, maculopapular drug rash	2-7 days after cutaneous drug exposure

Histamine Receptors + Effects

• Activation of H1 receptors causes: (main focus)

  • itching, stimulates secretion from nasal mucosa.

  • Contraction of bronchial smooth muscles.

  • CNS: H1 receptors inhibit appetite and increase wakefulness.

  • H1 and H2: Cooperate to induce vascular capillary dilation.

  • H1: Increased vascular permeability.

• Activation of H2 receptors causes:

  • Gastric acid secretion and H2 receptors may work with H1 receptors in certain types of hypersensitivity reactions.

• Activation of H3 receptors causes:

  • resynaptic H3 receptors function as autoreceptors for histaminergic neurons.

  • H3 receptor antagonists promote wakefulness.

• Activation of H4 receptors causes:

  • Chemotaxis of immune cells and secretion of proinflammatory cytokines

	H1	H2	H3	H4
G protein coupling (second messengers)	Gq (increased cytosolic calcium, increased NO and cGMP)	Gs (increased cAMP)	Gi (reduction in cAMP)	Gi (reduction in cAMP, increase in calcium)
Distribution	Smooth muscle, endothelial cells, CNS	Gastric parietal cells, cardiac muscle, mast cells, CNS	CNS, pre and postsynaptic	Cells of hematopoietic systems
Drugs that are inhibitors of receptor activation	Antihistamines (1st and 2nd gen)	Ranitidine	Pitolisant (indicated for narcolepsy)	N/A

Epinephrine

Physiological Histamine Antagonist

• Antagonizes the effect of H1, mediated bronchial smooth muscle contraction and vasodilation

• A1 receptor agonism: vasoconstriction → increased SNR and reduction in mucosal edema

• B1 receptor agonism: increase inotropy and HR (increases CO)

• B2 receptor agonism: bronchodilation and inhibition of further mediatory release from mast cells

Cromolyn Sodium and Nedocromil

• Mast Cell Stabillizers

• MOA: prevent mast cell degranulation and release of histamine and other mediators (mast cell degranulates → releases histamine + other cytokines)

  • Stabilize the membrane

• Use: Allergic rhinitis, allergic eye conditions

  • Conjunctivitis, keratitis

H1-Antihistamines

• H1 Inverse Agonists

• The H1 receptor is in an equilibrium between inactive and active state

  • Histamine when bound to H1 receptor → shifts equilibrium to the active state

  • H1 Inverse agonists bind to H1 receptor → shifts equilibrium to the inactive state

    • = decreased itching, vasodilation, vascular permeability

Chemical Class	First-Generation	Second Generation
Alkylamines	Chlorpheniramine
Piperazines (-zine)	Hydroxyzine, Meclizine, Cyclizine	Cetrizine, Levocetrizine
Piperidines	Cyproheptadine: serotonin antagonist properties → appetite stimulant, manages serotonin syndrome	Loratidine, desloratidine, fexofenadine
Ethanolamines (-amine)	Diphenhydramine, dimenhydrinate, doxylamine
Phenothiazine (-azine_	Promethazine
Other	Doxepin (also is a TCA)	Azelastine, Olopatadine (nasal spray and eye drops), Acrivastine + pseudoephedrine

Adverse Effects of 1st Gen Antihistamines

• CNS H1-receptors:

  • Decreased alertness, cognition, learning, memory and psychomotor performance

  • Increased impairment with/without sedation

• Muscarinic receptors (anticholinergic side effects):

  • Dry mouth

  • Urinary retention

  • Sinus tachycardia

• Serotonin receptors:

  • Increased appetite

  • Weight gain

• a-Adrenergic receptors:

  • Dizziness

  • Postural hypotension

• Cardiac Ion channels (Ikr, INa and others)

  • Increased QT interval

  • Ventricular arrhythmias

    • MOA: blocks muscarinic receptors in vagal nerve, so SA node is controlled by sympathetic nerves = increased heart rate

Other Uses for 1st Gen Antihistamines

• Motion Sickness: n/v, dizziness from motion

  • Pathophysiology: mediated by the inner ear (vestibular system) and increased cholinergic and histaminergic neurotransmission

  • Examples of drugs to prevent motion sickness:

    • Mecilizine, Dimenhydrinate (1st gen antihistamines)

    • Scopolamine (Muscarinic receptor antagonist)

• Management of acute dystonia (sudden involuntary muscle contractions) associated with central D2 receptor blockade

  • ex) Diphenhydramine (Benadryl) reduces effect b/c it acts as anticholinergic agent 

    • Blocks M1 receptors (ACh is the neurotransmitter)