Antihistamines Flashcards
Autocoid =
‘self-remedy’
Local hormone =
Chemical messenger formed by tissues on which it acts.
Where is histamine found?
High concentration in lungs, skin and smooth muscle (blood vessels)
Stored in basophils and mast cells
In granuoles
Rapidly inactivated by amine oxidase if not stored
Histamine in the stomach
Histamine found un histaminocytes
Histamine in the CNS
Histamine found in histaminergic neurones
Histamine in venom
Histamine found in toxics of venom
EG Insect stings and plant stings
Synthesis of Histamine
Synthesised from histidine (amino acid)
Release of Histamine from Mast cells: Acute inflammatory response
One of several mediators released in response to a pathogen. EG Bacteria or toxin.
Complement components -> C3a and C5a receptors -> Mast cell.
Pathogen -> Pathogen pattern receptors -> Mast cell
Release of Histamine from Mast cells: Hypersensitivity
Allergic immune system reaction to typical harmless substances. Harmless antigen (EG Pollen) -> Immunoglobulin (Ig) E Cell fixed antibody -> Mast cell
Release of Histamine from Mast cells: Physical destruction
Mast cell
Release of Histamine from CNS: Arousal pathways
Histaminergic neurones in TMN.
Spontaneously active and release histamine during wakefulness.
Release of Histamine from CNS: Emetic centre
Histaminergic neurones in TMN also receive input from vestibular centre in inner ear (spatial orientation) and other sensory inputs.
If mismatch between inputs = Activate histaminergic neurones = Activate emetic (Vomiting) centre in medulla.
Histamine receptors
G-protein coupled receptors
H1: Myosin phosphorylation, vascular permeability, NFkB activation. Inside Ca2+ increases. H1 coupled to phospholipase C
H2: Proton pump function, gastric acid secretion. Increase in inside cAMP. Coupled to adenylate cyclase.
H3/H4: Proton pump function, gastric acid secretion. decrease in inside cAMP. Coupled to adenylate cyclase.
Histamine receptor functions (H1)
CNS neuronal activation Nasal and bronchial mucus secretion Smooth muscle contraction Sensory nerve endings Proinflammatory cytokine secretion
Histamine receptor functions (H2)
Stimulation of gastric acid secretion
Cardiac stimulation - Chronotropic (time change), increase HR
Histamine receptor functions (H1 and H2)
Capillary permeability and dilation
Cardiac stimulation - Inotropic (time change), increase heart contraction
Histamine receptor functions - Pathologies
Allergic reaction: mild to severe. Immune system hypersensitive response to typically harmless substance in environment. EG Pollen or food Release of histamine from mast cells Can be localised
Allergic rhinitis
Inflammation inside nose in response to allergen EG Pollen or dust Very common (1 in 5) Can be localised immune response Sneezing, itchiness, runny nose Sensory nerve ending stimulation Increase nasal secretions Capillary permeability and dilation
Urticaria (hives)
Skin rash in response to allergen or toxic substance. EG Nettle sting, latex Itchy, raised bump, redness, pain Sensory nerve ending stimulation Capillary permeability and dilation Can be localised response
Moderate allergic reaction to allergen. EG food
1. Rhinitis conjunctivitis Sensory nerve ending stimulation Increase secretion Capillary permeability and dilation 2. Hives Sensory nerve ending stimualtion Capillary permeability and dilation 3. Tummy pain/diarrhoea Intestinal muscle contraction 4. Wheezing/chest tightness/shortness of breath Bronchiole contraction
Severe allergic reactions (Anaphylaxis)
Reapid onset
Breathing difficulties
Rapid HR
Loss of conciousness
Motion sickness
Sensory input (visual)
Spatial orientation (vestibular system in inner ear)
Input mismatch at Tuberomamillary nucleus
Histamine released to Emetic centre
Contraction of stomach muscles
Motion sickness
Antihistamines: 1st generation - Prophylaxis
Much more effective if given before histamine receptor stimulation to prevent development of symptoms
Antihistamines: 1st generation - Receptors
Typically H1 receptor antagonists
Can be muscarinic cholinergic receptor antagonists
Particularly diphenhydramine and promethazine
Can be α1-adrenoceptor antagonists
Particularly promethazine
Antihistamines: 1st generation - Examples
Hydroxyzine
Promethazine
Diphenhydramine
Antihistamines: 1st generation - Pros
Inexpensive and effective.
Decrease allergy / inflammation
Cross the BBB so can prevent motion sickness (Block H1 receptors in Emetic centre)
Cross the BBB so can cause sedation (Block H1 receptors in arousal pathway/cerebral cortex)
Not very H1 selective = extra unwanted effects
Antihistamines: 1st generation - Cons
Cross the BBB = Unwanted sedation (BLock H1 receptors in arousal pathway/cerebral cortex)
May potentiate other CNS depressants
? Paradoxical hyperactivity in children (diphenhydramine)
Not very H1 selective = Unwanted adverse effects
Antihistamines: 1st generation - Parasympathetic activation
Pupils constrict Lens of eye readjust for closer vision HR decrease Salivary secretions normalise Bladder contraction
Antihistamines: 1st generation - Effect of muscarinic antagonists
Pupils dilate (relaxation of constrictor pupillary muscle - blurred vision)
Increased cardiac output (rate and force)
Decreased exocrine gland secretion (dry mouth)
Decreased bladder contraction (urinary retention)
But muscarinic receptor antagonism therapeutic value = Antiemetic effects
Antihistamines: 1st generation - Can exacerbate anticholinergic adverse effects other drugs, Example.
EG Monoamine oxidase inhibitors or decrease effectiveness of cholinergic drugs.
EG Rivastigmine in Alzheimers.
Antihistamines: 1st generation - Sympathetic activation
Vasoconstriction (α1-adrenoreceptor)
Antihistamine: 1st generation - Effect of α1-adrenoreceptor antagonist
Vasodilation (hypotension, dizziness)
Antihistamine: 1st generation - Diphenhydramine also affects 5-HT neurotransmission
1960's discovered inhibited 5-HT reuptake. Search for antidepressants with similar structure but fewer side effects. SSRI Fluoxetine (Prozac) formed.
Antihistamine: 2nd generation - Examples
Cetirizine (partially sedating)
Loratidine (non-sedating)
Fexofenadine (non-sedating)
Antihistamine: 2nd generation - Features
Add carboxyl groups = More polar
Do not cross BBB as easily
Less unwanted sedation
Less anticholinergic effects
Antihistamine - H1 Pharmacokinetics
Absorption -> Oral Cmax 1-2 hours Distribution -> 1st gen = All tissues 2nd gen = All tissues except CNS Metabolism -> 1st gen = cytochrome P450s 2nd gen = most cytochrome P450s, not cetirizine Elimination -> Average half life 4-6 hours
Antihistamines H1 receptor antagonist summary - Theraputic uses
Decreases allergy and inflammatory response
Decrease motion sickness / nausea
Increase sedation
Antihistamines H1 receptor antagonist summary - Adverse effects
Sedation (1st gen)
Dry mouth, urinary retention, blurred vision (anticholinergic)
Hypotension, dizziness (antiadrenergic)
Antihistamines H1 receptor antagonist summary - Not used to treat asthma
Additional chemical mediators involved in bronchial contraction
Antihistamines H1 receptor antagonist summary - Not used to treat anaphylaxis
Adrenaline used
Activation of β2-adrenoceptors = bronchiole muscle relaxation
Activation of β1-adrenoceptors = increase cardiac rate and force
Activation of α1-adrenoceptors = vasoconstriction
Antihistamines: H2 receptor antagonist - Gastric acid secretion
Stomach -> Gastric gland -> Parietal cell -> Chloride co-transported (Cl- goes out of cell, into lumen), Proton pump H+K+ATPase (H+ goes out, into lumen) -> Release HCL (pH <1)
Antihistamines: H2 receptor antagonist - Peptic ulcers and GERD
Promote peptic ulcer healing
Peptic ulcers = Perforation in the lining of the small intestine or stomach
Infection with gram-negative Heliobacter pylori
Use of NSAIDs (COX2 flashback)
Reduce gastropharengeal reflux disease (heartburn)
Antihistamines: H2 receptor antagonist - Antimicrobials eradicate H.pylori
Treatment to reduce gastric secretion
H2 antagonists competitively block histamine binding (fully reversible)
Reduced gastric acid secretion by up to 70%
Cimetidine and Ranitidine
Also, Nizatidine and Famotidine
Antihistamines: H2 adverse effects - Pros
All 4 effective for H. Pylori peptic ulcers
Effective for heartburn
Inexpensive
Relatively safe
Antihistamine: H2 adverse effects - Cons
Peptic ulcer reoccurence common in H.pylori is present and not treated.
Not as effective treating and preventing NSAID induced peptic ulcers.
Heartburn onset of action in 45mins.
They can reduce efficacy of drugs requiring acidic environment for absorption.
Cimetidine affects metabolism of other drugs.
Antihistamines - H2 receptor antagonists alternates
Proton pump inhibitors (PPIs)
Decrease H+ secretion
Dexlansoprazole omeprazole
Prodrug
Acid resistant coating Coating removed in duodenum Absorbed and transported to parietal cell Metabolised to activate drug there Binds to H+K+ATPase Gastric acid secretion decreases 18 hours to resynthesise
Prodrug - Pros
Higly effective
Long duration
Prodrug - Cons
Delayed onset of action
Increased risk of gut infection (C.defficile)
Gut pH substantially above physiological level
