The histaminergic system and antihistamines

What are autacoids?

• Local hormones

Short-acting endogenous mediators

• Often involved in the inflammatory response

Give examples of important autacoids.

• Bradykinin

• Eicosanoids: prostaglandins, thromboxanes, leukotrienes

• Histamine

Where is histamine an endogenous substance synthesized, stored, and released?

• Mast cells: abundant in skin, GI tract, respiratory tract

• Basophils: in the blood

• Neurons: in CNS and PNS, acting as a neurotransmitter

How is histamine synthesized, stored, released, and metabolized?

• Synthesis: decarboxylation of histidine via histidine decarboxylase (HDC)

• Storage: in granules of mast cells, basophils, enterocytes

• Release: triggered by stimuli via Ca²⁺-dependent exocytosis

• Metabolism: eliminated by oxidative deamination and/or transmethylation

Where is the H1 receptor found and what are its functions?

• Location: smooth muscle, endothelium

• Functions: bronchoconstriction, vasodilation, separation of endothelial cells, pain & itching

• Involved in allergic rhinitis and motion sickness

Where is the H2 receptor found and what are its functions?

• Location: gastric parietal cells, vascular smooth muscle

• Functions: regulate gastric acid secretion, vasodilation, inhibit IgE-dependent degranulation

• Acid reflux

Where is the H3 receptor found and what are its functions?

• Location: CNS

• Functions: presynaptic feedback inhibition of histamine synthesis and release

Where is the H4 receptor found and what are its functions?

• Location: bone marrow, white blood cells

• Functions: mediate mast cell chemotaxis

What G-protein is H1 receptor coupled to and its downstream effect?

• Gq coupled to PLC

• Downstream: activates Phospholipase C (PLC) → IP₃/DAG pathway → Ca²⁺ mobilization

What G-protein is H2 receptor coupled to and its downstream effect?

• Gs coupled to AC

• Downstream: activates Adenylyl Cyclase (AC) → increases cAMP

What G-protein is H3 receptor coupled to and its downstream effects?

• G-protein: Gi/o coupled to AC

• Downstream: inhibits Adenylyl Cyclase, opens K⁺ channels, reduces Ca²⁺ influx

• Function: inhibits presynaptic neurotransmitter release

What G-protein is H4 receptor coupled to and its downstream effects?

• G-protein: Gi/o (in mast cells & eosinophils)

• Downstream: can trigger Ca²⁺ mobilization → mediates mast cell chemotaxis

What is the Lewis triple response of histamine in the skin?

• 1. Red line: initial capillary dilation at the site of stroking

• 2. Flare: surrounding arteriolar dilation due to axon reflex

• 3. Wheal: localized edema from increased capillary permeability

What causes the red spot in the histamine triple response?

• Appears within seconds

• Caused by direct vasodilation of capillaries

• H1 receptor mediated

What causes the flare in the histamine triple response? 4

• Appears ~1 cm beyond the red spot

• Caused by axon reflexes → indirect vasodilation

• Produces itching

• H1 receptor mediated

What causes the wheal in the histamine triple response?

• Appears 1–2 minutes after injection, same area as the red spot

• Due to edema from increased capillary permeability

• H1 receptor mediated

How does histamine affect cardiac contractility?

• Increases force of contraction in atria and ventricles

• Promotes Ca²⁺ influx

• Mainly mediated by H2 receptors via cAMP accumulation

How does histamine affect heart rate?

• Speeds heart rate by increasing diastolic depolarization in the SA node

• Mainly H2 receptor mediated via cAMP

ow does histamine affect AV conduction and arrhythmias?

• Slows AV conduction (mainly H1 receptor)

• Increases automaticity

• High doses can elicit arrhythmias

Why are direct cardiac effects of histamine sometimes masked during IV administration?

• Baroreceptor reflexes triggered by reduced blood pressure

• Reflexes can override the direct effects of histamine on the heart

What is the effect of H1 receptors on bronchial smooth muscle? Effects on human lung

• Bronchoconstriction

• Increased mucus viscosity

What is the effect of H2 receptors in the lung?effect on human lung

• Slight bronchodilation

• Increased mucus secretion

How does H1 receptor activation affect vagal sensory nerve endings in the lung? Effect on human lung

Stimulates cough reflex

How does histamine affect blood vessels and vascular resistance? Effects of histamine

• Decreases peripheral vascular resistance (H1 & H2) → flushing, headache

• Increases vascular permeability (H1) → local edema, especially in postcapillary venules

How does histamine affect the nervous system?

Stimulates nerve endings (H3) → pain

How does histamine affect the heart? Effects of histamine

• Tachycardia via direct H2 receptor action and reflex

How does histamine affect secretions and smooth muscle?effects of histamine

• Increased mucus production (airways)

• Gastric acid & pepsin secretion (H2)

• Increased GI motility (H1)

What are some pathophysiological actions of histamine? 4

• Mediates immediate hypersensitivity reactions and acute inflammation

• Anaphylaxis

• Seasonal allergies

• Contributes to duodenal ulcers

What factors can promote histamine release?

• Therapeutic drugs: morphine (itch), vancomycin (“red neck syndrome”)

• Experimental compounds

• Antigen-antibody reactions: immune complex-mediated activation of mast cells/basophils

• Unknown causes: e.g., hives with no identified trigger

What type of allergic reaction is anaphylaxis and how is it mediated?

• Type I allergic response (immediate hypersensitivity)

• Mediated by IgE antibodies

• IgE binds mast cells and basophils

What happens when IgE binds antigen during anaphylaxis?

• Fab portion of IgE binds antigen

• Causes release of histamine, leukotrienes, prostaglandins, etc.

• Reactions range from mild allergy to anaphylactic shock

What are the main physiological effects of anaphylaxis?

• Decreased blood pressure

• Decreased cardiac output

• Bronchoconstriction and increased pulmonary secretions

• Pruritis (itching)

What is the primary treatment for anaphylaxis and why?

• Epinephrine (not initially antihistamines)

• Acts as a physiological antagonist of histamine

• Effects: α₁ → vasoconstriction, β₁ → ↑ heart rate, β₂ → bronchodilation

Three mechanistically different approaches to minimize histamine reactions:

• Physiological antagonism (e.g. adrenalin)

• • Inhibit the release of histamine

• • Pharmacological antagonism (antihistamines)

What are the main classes of histamine-related drugs?

• Mast cell stabilizers: Cromolyn

• H1 receptor antagonists: 1st and 2nd generation antihistamines

• H2 receptor antagonists: Ranitidine

H3 receptor antagonists: Pitolisant

What are the general properties and uses of first-generation H1 antihistamines? 5

• Adjunct in anaphylaxis (use with H2 antagonists & epinephrine)

• Antiallergy

• Sedative

• Prevent motion sickness (antiemetic)

• Antitussive

What are the pharmacokinetic properties of first-generation H1 antihistamines?

• Lipid soluble → cross BBB and placenta easily → CNS effects

• Well absorbed orally

• Metabolized in the liver

What are the common adverse effects of first-generation H1 antihistamines?

• CNS: sedation, drowsiness, headache

• GI: nausea, vomiting, constipation, diarrhea

• Other: dry mouth, blurred vision, urinary retention, cough

What structural features of second-generation H1 antihistamines reduce CNS effects?

• Lipid-soluble core with a highly ionized functional group

Less CNS penetration → primarily peripheral H1 antagonism

reducing BBB penetration and thus limiting CNS H1 blockade, resulting in fewer sedative effects.

What are the advantages of second-generation H1 antihistamines?

• Avoids drowsiness of first-generation H1 antihistamines

• Fewer adverse reactions compared to injected corticosteroids

What are the pharmacokinetics of second-generation H1 antihistamines?

• Well absorbed

• Excreted mainly unmetabolized, primarily via urine

• Metabolised in the liver

• Can induce CYP450 liver enzymes

What are the actions and therapeutic uses of the H3 receptor antagonist Pitolisant?

• Enhances brain histaminergic neuron activity

• Promotes wakefulness → reduces excessive daytime sleepiness (EDS)

• Reduces cataplexy

• Treats idiopathic hypersomnia