Histamine
1st Immediate Response
Transient Response
Stored in Mast cells and Basophils
Releasing Agent needed (Morphine can displace histamine from protein complex within cells)
Combines with 4 specific cell membrane receptors (H1-H4)
Histamine Receptor
H1 - GPCR; Vasodilation, Edema, Vascular Permeability;
Acts on sensory nerves and elicits itching and discomfort
H1 Receptor
Smooth m., Endothelial cells, Sensory n., CNS
Chlorpheniramine antagonist
Antagonist = Inverse Agonists
Stabilize inactive form of H1 receptor on effector cells (Block constitutive histamine action)
H2 Receptor
Gastric parietal cells, Cardiac and Smooth m., Mast cells, CNS
Ranitidine antagonist
H3 Receptor
CNS: presynaptic, myenteric plexus
Thioperamide antagonist
H4 Receptor
Cells of hematopoietic origin
Epinephrine
Physiologic Antagonist
Agonist at alpha and beta adrenergic receptors
Vasoconstriction
Airway smooth muscle relaxation
Antihistamine Actions
Vascular Smooth m. - Indirect by inhibit NO production by endothelium; Histamine to pre capillary dilation, post capillary constriction to edema and immediate vasodilation (H1)
Endothelial cells - Prevent increase permeability
Sensory nerve ending - Prevent itching
Mucus glands - Prevent increased secretion
Airway Smooth m. - Prevent histamine contraction (Not useful in asthma)
GI Smooth m. - Prevent histamine contraction
CNS receptors - Antagonize histamine waking
Histamine and Waking
Cells Located Tuberomammillary Nucleus (TMN) in Posterior Hypothalamus; Diffuse projections to cerebral cortex, striatum, hippocampus and LDT/PPT; Histaminergic TMN and GABAergic VLPO in Ant. hypothalamus are antagonistic, TMN inhibits VLPO and VLPO inhibits TMN; Sedating
Other H1 Property Drugs
Antipsychotics 1st and 2nd gen Tricyclic Antidepressants (Not selectives) Antiserotonergics - Cyproheptidine Antidopaminergic - Prochorperazine Antimuscarinic - Benzotropine
Antihistamine Cardiac
Bind to and inhibit hERG (KCNH2) Kv 11.1 potassium channels
hERG K - Primary repolarization ion channel in heart and block produces long QT interval and might cause cardiac arrhythmia
Torsades de pointes - Fatal
Antihistamines (Astemizole) - Cardiac toxicity and deaths
Antihistamines w/P450 inhibitors increase toxicity
2nd generation - Low drowsiness, Withdrawn (Older block hERG but drowsiness limit)
Antihistamine Other Effects
Atypical antipsychotic drugs with strong antihistaminergic properties - Weight gain and diabetes worsen (Recent studies - Antiserotonergic and Anticholinergic receptors; Drug induced insulin resistance; CNS action - less prominent in 2nd gen agents)
Ethanolamines
Diphenhydramine (Benedryl, generic)
Antihistamine, First gen
Alkylamines
Chlorpheniramine (ChlorTrimeton, generic)
Antihistamine, First gen
Piperazines
Hydroxyzine (Atarax)
Antihistamine, First gen
Phenothiazines
Promethazine (Phenergan, generic)
Antihistamine, First gen
Antihistamine Pharmacokinetics and Side Effects (First Gen)
Pharmacokinetics: Good absorption from GI tract, Cross blood-brain barrier and placenta (hydroxyzine contraindicated), Onset at 1-2hrs, duration 3-6hrs of action w/in 30mins, Max effect, Metabolized in liver by CYP2D6 (some 2A6)
Side Effects: Intensity varies, CNS drugs with similar side effects; Sedation, Anti-cholinergic action, Little or no respiratory depression (OTC sleep aids), Hypersensitivity (Use with Epi to treat hypersensitivity rxn), Weight gain, Arrhythmias; Loss of effectiveness - Tolerance, Paradoxical CNS stimulation in children and overdose (No anesthesia may cause seizures)
Second Gen Prototypes
Antihistamines - Low Drowsiness
Loratadine (Claritin)
Fexofenadine (Allegra)
Desloratadine (Clarinex)
Antihistamine Pharmacokinetics and Side Effects (Second Gen)
Pharmacokinetics: Absorption altered if taken w/grapefruit juice (3A4), Little or no crossing blood brain barrier or placenta, Longer half life, Most metabolized in liver by CYP3A4, CYP2D6
Side effects: Cardiac arrhythmias - Astemizole, Terfenadine - High (2-10X) doses, Normal doses in patients w/ Ketoconazole, Troleandomycin, Erythromycin and other Macrolide antibiotics; Little or no sedation, Little or no anticholinergic action, Less diabetogenic action
Antihistamine Therapeutic Use
Prophylactically to prevent symptoms of allergy and anaphylaxis, Part of treatment in common cold, Sedative 1st gen (OTC sleep aids), Prophylactically to prevent motion sickness, Treat early Parkinsons disease (Primary 1st gen)
Antihistamine Use in Dentistry
Pre-procedural sedation (Promethazine, Hydroxyzine, Diphenhydramine) - Sedative and anxiolytic, Block actions of histamine being released by opiates, Decrease salivary secretions (anticholinergic effect), Act as antiemetic/anti gagging, Produce mild analgesia
Use of local anesthetic
Treat allergic lesions or oral mucosa
H1 Antihistamine Drug Interactions (First Gen)
Potentiate actions of other sedatives (Potentiate sedative actions of opiates - Opiate and antihistamine dose cut in half when drugs in combo)
P450 blockers impact actions
H2 Receptor Antagonists
Decreases actions of histamine by blocking H2 on effector cells
Effective in inhibiting Histamine action on gastric parietal cells (Vascular smooth m. - Direct - Delayed vasodilation; Cardiac m. - Direct - Histamine is ionotropic + chronotropic)
H2 Receptor Antagonist Prototypes
Cimetidine (Tagamet)
Famotidine (Pepcid)
H2 Receptor Antagonist Pharmacokinetics and Side-Effects
Pharmacokinetics: Rapid absorption from GI, Long duration of action - Administer hs or bid, Crosses placenta, Most excreted in urine
Side-effects: Dizziness, Mental confusion, Seizures
Cimetidine - High dose - Block androgen receptors to result in gynecomastia, impotence and galactorrhea
H2 Receptor Antagonist Drug Interactions
Cimetidine inhibits cytochrome P450 (1A2, 2C9, 2C19, 2D6, 2E1, 3A4); Inhibit metabolism of drugs like warfarin, theophylline, phenytoin, lidocaine, beta blockers, opiates (two mechs, also decreases hepatic blood flow)
H3 Receptor Antagonist
Auto receptors reduce release of histamine from histaminergic CNS nerves, Antagonists act as stimulants; Regional diff in basal ganglion, appear as postsynaptic receptors; H3 in 20 isoforms, Heteroreceptors regulate release of transmitter (Improve sleep, attention, learning, Treat narcolepsy, epilepsy, obesity, psychiatric disorders, Parkinsons, Alzheimers, neuropathic pain, Tourettes syndrome)
H4 Receptor Antagonist
Treat inflammatory conditions - Asthma, pruritus, allergic reactions, pain, neuro-inflammation, neuro-protection
