Histamine and Antihistaminics

Case study

• A 24 year old male patient John , suffers from allergic rhinitis. Every winter, she develops a runny nose, itchy eyes, and sneezing.

• To relieve his symptoms, he takes an over-the-counter antihistamine, diphenhydramine.

• John is annoyed by the unpleasant effects that accompany his allergy medication. Every time he takes his antihistamine, he feels drowsy and his mouth feels dry.

• He makes an appointment with his doctor who, advises him to take loratadine. Upon taking new allergy medication, his symptoms are relieved and he experiences no drowsiness or other adverse effects.

Questions

• Why does John develop seasonal rhinitis?• Why does diphenhydramine relieve John`s

symptoms?• Why does diphenhydramine cause

drowsiness?• Why doesn't loratadine cause drowsiness?

Histamine

• Histos: Tissue

N N

NH2

H

1

2

3

45

Histamine

•Present mostly in mast cells: skin, lungs, GIT Mucosa •Non mast cell histamine: Brain, Gastric Mucosa

Histamine is a biogenic amine present in many animal and plant tissues .

Histamine

• Biogenic amine present in many animal and plant tissues

• Also present in venoms and stinging secretions • One of the mediators involved in

inflammatory & hypersensitivity reactions.

Synthesis, storage & metabolism of histamine

• Synthesized by decarboxylation of amino acid histidine

• Histamine is present in storage granules of mast cells & also found in skin, lungs, liver, gastric mucosa etc.

Mechanism of Action of Histamine

Histamine

H1 Receptors H2 Receptors H3 Receptors (presynaptic auto

receptors)

↑ Ca2+

Smooth muscle contractionIncreased capillary permeability Vasodilation Sensory nerve endings pain & itching

↑ cAMP

↑ Gastric acid secretion Blood vessels: vasodilation Increased capillary permeability

↓ histamine release ↓secretion Vasodilation

↓ cAMP

Pharmacological actions

• CVS: – Dilates arterioles, capillaries, venules, • IV injection- decreased BP• Intradermal- Triple response

Stimulating H1, H2, H3 Receptors

Red spot

Wheal

Flare(Reflex arteriolar dilatation)

Pharmacological actions (Contd)

• Visceral smooth muscles:– Bronchospasm, abdominal cramps

• Secretions:– Increased gastric secretion (H2)

– Increased nasal secretions (H1)

• Sensory Nerve Endings: Itching • CNS:– Wakefulness on intra Cerebroventricular Injection

Therapeutic Uses

• Betahistine – To control vertigo in Meniere`s disease 8 mg tab ½

tablet QID

Histamine releasers • stings and venom •Ag-Ab reaction •Drugs d-tubocurarine Morphine

Adverse effects of histamine release

• Itching, Urticaria • Flushing • Hypotension • Tachycardia • Bronchospasm • Angioedema• Wakefullness • Increased acidity (Gastric acid secretion)

Classification of H1 Antagonists

Mechanism of action

Competitive antagonism

Histamine General formula of H1 Blocker

Pharmacological actions • CNS depression: (More with first generation)– Sedation and drowsiness– Some have antiemetic and antiparkinsonian

effects • Antiallergic action• Anticholinergic actions (More with first

generation)– Dryness of mouth , Blurring of vision– Constipation – Urinary retention

Pharmacological Actions

• Antimotion sickness effect: Dimenhydrinate, Promethazine

• Antiemetic: Promethazine • Antiparkinsonism: Diphenhydramine,

orphenadrine, promethazine(IV) • Antivertigo: cinnarizine

Preparations & dosage (Daily)Drug Dose

1. Diphenhydramine 25-50 mg oral 2. Dimenhydrinate 25-50 mg oral 3. Promethazine 25-50 mg oral/injection 4. Chlorpheniramine 2-4 mg oral5. Pheniramine 25- 50 mg oral/im 6. Cinnarizine 25-150 mg oral 7. Cyprohepatidine 4 mg oral

Therapeutic uses

1. Allergic rhinitis & common cold 2. Allergic dermatitis, itching, urticaria 3. Wasp stings/ bite: pain and itching decreases 4. Mild blood transfusion reactions 5. Allergic conjunctivitis 6. Motion sickness: dimenhydrinate, promethazine 7. Morning sickness: promethazine

8. Vertigo: cinnarizine 9. Chronic urticaria10. Appetite stimulant: cyprohepatidine 11.Drug induced parkinsonism: Diphenhydramine,

Therapeutic uses (Contd..)

Adverse effects

• Sedation • Anticholinergic effects• Dermatitis on local use • Cyclizine, meclizine : teratogenicity

Second generation H1 Blockers(Non Sedative:Less anticholinergic property)

• Fexofenadine• Astemizole • Loratidine • Cetrizine • Levocetrizine• Azelastine • Terfenadine

Uses: • Allergic rhinitis • Allergic Dermatitis• Allergic conjunctivitis • Urticaria • Common cold

Advantages of second generation antihistaminics

• They have no anticholinergic side effects• Do not cross blood brain barrier (BBB), hence

cause minimal or no drowsiness and sedation • Do not impair Psychomotor performance

Drug interactions

• Increased effect of CNS depressants• MAO inhibitors increase anticholinergic effect

of antihistaminics • First generation antihistaminics can decrease

effectiveness of cholinesterase inhibitors used in Alzheimer`s disease like donepezil and rivastigmine

Answers

• The IgE-mediated hypersensitivity reaction is responsible for initiation of certain inflammatory disorders, like allergic rhinitis .

• John suffered from allergic rhinitis, with a runny nose, itchy eyes, and sneezing.

• An environmental allergen, such as pollen, crosses the nasal epithelium and enters the underlying tissue. There, the allergen encounters previously sensitized mast cells and crosslinks IgE/Fc receptor complexes on the mast cell surface.

• The mast cell degranulates and releases histamine, which binds to H1 receptors in the nasal mucosa and local tissues.

Answers

• Stimulation of H1 receptors causes blood vessel dilation and ↑es vascular permeability, leading to edema. This swelling in the nasal mucosa is responsible for the nasal congestion experienced in allergic rhinitis.

• The accompanying itching, sneezing, runny nose, etc result from the combined action of histamine and other inflammatory mediators, including kinins, prostaglandins etc.

• These molecules initiate the hypersecretion and irritation characteristic of allergic rhinitis.