Published on February 16, 2014
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 NH2 5 H skin, lungs, GIT Mucosa 4 3 1 N N •Present mostly in mast cells: 2 •Non mast cell histamine: Brain, Gastric Mucosa Histamine 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 ↑ Ca2+ Smooth muscle contraction Increased capillary permeability Vasodilation Sensory nerve endings pain & itching H2 Receptors ↑ cAMP ↑ Gastric acid secretion Blood vessels: vasodilation Increased capillary permeability H3 Receptors (presynaptic auto receptors) ↓ cAMP ↓ histamine release ↓secretion Vasodilation
Pharmacological actions Stimulating H1, H2, H3 Receptors • CVS: – Dilates arterioles, capillaries, venules, • IV injection- decreased BP • Intradermal- Triple response 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 1. 2. 3. 4. 5. 6. 7. Dose Diphenhydramine Dimenhydrinate Promethazine Chlorpheniramine Pheniramine Cinnarizine Cyprohepatidine 25-50 mg oral 25-50 mg oral 25-50 mg oral/injection 2-4 mg oral 25- 50 mg oral/im 25-150 mg oral 4 mg oral
Therapeutic uses 1. 2. 3. 4. 5. 6. Allergic rhinitis & common cold Allergic dermatitis, itching, urticaria Wasp stings/ bite: pain and itching decreases Mild blood transfusion reactions Allergic conjunctivitis Motion sickness: dimenhydrinate, promethazine 7. Morning sickness: promethazine
Therapeutic uses (Contd..) 8. Vertigo: cinnarizine 9. Chronic urticaria 10. Appetite stimulant: cyprohepatidine 11.Drug induced parkinsonism: Diphenhydramine,
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.
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