2024 histamines antihistamines.pdf

PHARMACOLOGY 2 HISTAMINE & ANTI-HISTAMINE Ms Salopuka Basic Medic Sciences 18th Sept, 2024  Learning outcomes The student should be able to: Gain an understanding of: – what histamine is and its physiological functions; – the respective receptors and...

PHARMACOLOGY 2 HISTAMINE & ANTI-HISTAMINE Ms Salopuka Basic Medic Sciences 18th Sept, 2024  Learning outcomes The student should be able to: Gain an understanding of: – what histamine is and its physiological functions; – the respective receptors and how their effect on various functions Know what anti-histamines are, their drug examples; and the receptors they interact with to exert their p’cological effects & the possible adverse effects.  Introduction Histamine is a biological amine It is a hydrophilic molecule & is made up of an imidazole ring & an AA connected by two methylene groups Histamine is a neurotransmitter found in non- neural tissue Also occurs in plant & animal tissues; & a component of some venoms & stinging secretions.  Cont.. Most tissue histamine is bound in granules (vesicles) in mast cells or basophils. Histamine content of many tissues directly related to mast cell content. Bound form of histamine biologically inactive Stimuli triggers release of mast cell histamine, allowing free amine to exert its actions on surrounding tissues. Mast cells are concentrated at sites of potential tissue injury (in nose, mouth & feet; internal body surfaces & blood vessels).  Histamine receptor subtypes (from Basic & Clinical Pharmacology 10th ed. By Vishal) Receptor Partially Postreceptor Partially Selective Subtype Distribution Selective Mechanism Agonists Antagonists Smooth muscle, Mepyramine, H1 Gq, ↑ IP3, DAG Histaprodifen endothelium, brain triprolidine Gastric mucosa, Ranitidine, H2 cardiac muscle, mast Gs, ↑ cAMP Amthamine tiotidine cells, brain Presynaptic: brain, R-a- Thioperamide, H3 myenteric plexus, Gi, ¯ cAMP Methylhistamine, iodophenpropit, other neurons imetit, immepip clobenpropit1 Eosinophils, Clobenpropit, H4 neutrophils, CD4 T Gi, ¯ cAMP Thioperamide imetit, clozapine cells  Mechanism of action Histamine exerts its actions by combining with specific cellular receptors located on surface membrane. All four receptor types are coupled with G proteins (GPCR). Structures of H1 & H2 receptors differ significantly, more closely related to muscarinic & 5-HT1 receptors respectively than to each other. H4 receptor is homologous with H3 receptor but does not seem to be closely related to any other histamine receptor.  Cont.. A single molecule may be an agonist at one histamine receptor & an antagonist at another. E.g. Clobenprobit, an agonist at H4 receptors, is an antagonist or inverse agonist at H3 receptors. In the brain, H1 & H2 receptors are located on postsynaptic membranes H3 receptors are predominantly presynaptic.  Cont.. H1 receptors – present in endothelium, smooth muscle cells, & nerve endings – elicit ↑ in phosphoinositol hydrolysis & an ↑ in IC Ca2t. H2 receptors – present in gastric mucosa, cardiac muscle cells & some immune cells – increase IC cyclic adenosine monophosphate (cAMP) via Gs. – those coupled to Gq, activate IP3-DAG (inositol 1,4,5- trisphosphate-diacylglycerol) cascade under certain circumstances.  Cont.. H3 receptors: – reduce transmitter release from histaminergic & other neurons – ? mediated by ↓ in Ca influx through N-type Ca channels in nerve endings. H4 receptors – mainly found on leukocytes in bone marrow & circulating blood. – have chemotactic effects on eosinophils & mast cells → role in inflammation and allergy; – modulate production of these cell types & may mediate recognized effects of histamine on cytokine production.  Physiological functions of histamine Mediator of immediate allergic & inflammatory reactions Associated with gastric acid secretion Functions as a neurotransmitter & neuromodulator Plays a role in chemotaxis of WBC (newer evidence) Produces physiologic & pathologic effects through multiple receptor subtypes often released locally → an autacoid or local hormone No clinical application in Rx. of disease BUT Comp’ds that selectively activate certain receptor subtypes or selectively antagonize their actions are clinically useful  Chemical & mechanical release Drugs such as morphine and tubocurarine (amines), can displace histamine from the heparin-protein complex within cells. No energy required for release & is not associated with mast cell injury or degranulation. Loss of granules from mast cell also releases histamine, since Na+ in ECF rapidly displace amine from the complex. Chemical & mechanical mast cell injury → degranulation & histamine release.  Non-mast cell histamine Found in several tissues including brain where it fxns as neurotransmitter. Endog. neurotransmitter histamine; responsible for brain fxns e.g., – neuro-endocrine control – CV regulation – thermal & body wght regulation – arousal Another non-neuronal site of histamine release: – enterochromaffin-like (ECL) cells of fundus of the stomach. – ECL cells release histamine as 1⁰ gastric acid secretagogue (activate acid-producing parietal cells of the mucosa).  Clinical p’cology of histamine Clinical Uses – Histamine aerosol – used in pulmonary function labs – provocative test (bronchial hyper-reactivity) Adverse effects (dose-related) – flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction & GI upset (scombroid fish poisoning: due to histamine produced by bacterial action on the flesh of the fish) Contraindications – Should not be given to patients with asthma (except for testing of pulmonary function) or to patients with active ulcer disease or GI bleeding.  Histamine antagonists Physiologic antagonists e.g., adrenaline injection – Lifesaving in systemic anaphylaxis Release inhibitors ↓ degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction Examples: – cromolyn & nedocromil in Rx of asthma. – B2-adrenoceptor agonists ↓ histamine release.  Cont.. Histamine receptor antagonists Competitively antagonize many actions of histamine on smooth muscle. Selective H2-receptor antagonists → more effective therapy for peptic disease. Selective H3 & H4 antagonists Potent & selective experimental H3-receptor antagonists – Examples: thioperamide & clobenpropit Some H1 antihistaminic drugs in clinical use (from Basic & Clinical Pharmacology 10th ed. By Vishal) FIRST GENERATION ANTIHISTAMINES Usual Adult Anticholinergic Drugs Comments Dose Activity Ethanolamines Carbinoxamine 4 – 8mg +++ Slight to moderate sedation Dimenhydrinate (salt 50mg +++ Marked sedation; anti-motion of diphenhydramine) sickness activity Diphenhydramine 25 – 50mg +++ Marked sedation; anti-motion (prototype) sickness activity Ethylaminediamine tripelennamine 25 – 50mg + Moderate sedation Piperazine derivatives hydroxyzine 15 – 100mg no data Marked sedation cyclizine 25 – 50mg _ slight sedation; anti-motion sickness activity Slight sedation Alkylamines Brompheniramine 4 – 8mg + Slight sedation Chlorpheniramine 4 – 8mg + slight sedation; common component of OTC “cold” medication  Cont..H1 antihistamine drugs cont..(from Basic & Clinical Pharmacology 10th ed. By Vishal) FIRST GENERATION ANTIHISTAMINES cont... Drugs Usual adult dose Anticholinergic action Comments Phenothiazine deriv promethazine 10 – 25mg +++ marked sedation; (prototype) antiemetic; α-block Miscellaneous ciproheptadine 4mg + moderate sedation; also has anti-serotonin activity SECOND GENERATION ANTIHISTAMINES Drugs Usual adult dose Anticholinergic action Comments Piperidine Fexofenadine 60mg _ Miscellaneous loratidine (Claritine) 10mg _ longer action cetrizine (Zyrtec) 5 – 10mg _  Cont.. P’kinetics – rapidly absorbed after oral admin – peaks in blood 1-2 hrs – widely distributed, 1st -gen drugs enter CNS readily – some extensively metabolized primarily by microsomal systems in liver – several 2nd -gen agents metab. by CYP3A4 – risk for interactions when other drugs (such as ketoconazole) inhibit this subtype of P450 enzymes  Pharmacodynamics Histamine receptor blockade H1-receptor antagonists block actions of histamine by reversible competitive antagonism at H1 receptor. Negligible potency at H2 receptor & less potency at H3 receptor; – e.g. histamine-induced contraction of bronchiolar or GI smooth muscle completely blocked by these agents – effects on gastric acid secretion & heart are not modified.  Clinical uses Allergic reactions prevent or treat symptoms of allergic reactions drugs of choice for allergic rhinitis & urticaria & quite effective hay fever & drugs selected with the goal of minimizing sedative effects Nausea & vomiting (assoc. w/pregnancy) H1-antagonist drugs studied for possible use in Rx of "morning sickness”. Piperazines withdrawn due to teratogenic effects in rats  Cont’d.. Motion sickness & vestibular disturbances prevention of motion sickness; drug e.g., diphenhydramine & promethazine. H1 antagonists more effective in preventing motion sickness when combined with ephedrine or amphetamine.  Adverse effects Most common undesirable effects: sedation & antimuscarinic actions Less common toxic effects of systemic use: excitation & convulsions in children postural hypotension & allergic responses  H2-receptor antagonists ↑ incidence of peptic ulcer disease & related GI complaints led to an interest in potential of these H2- receptor antagonists. this class of drugs are able to ↓ gastric acid secretion & their low toxicity – → most frequently used drugs in US – → have become OTC items  Cont.. No selective H3 or H4 ligands currently available for clinical use. Selective H3 ligands may be useful in: – sleep disorders – obesity & cognitive – & psychiatric disorders H4 blockers: – chronic inflammatory conditions e.g., asthma  Summary Histamine is a biological amine. It is a neurotransmitter found in non-neural tissue. It exerts its actions by combining with specific cellular receptors (H1 – H4) located on surface membrane. It can be an agonist at one histamine receptor & an antagonist at another. Histamine antagonists are: Physiologic antagonists e.g., adrenaline inj Release inhibitors e.g., cromolyn Histamine receptor antagonists e.g.,thioperamide, clobenpropit (H3)  References 1. Basic & Clinical Pharmacology 10th ed. (2007), electronic by Visha 2. Goodman & Gilman’s The pharmacological Basis of Therapeutics, 11th edition, e-book 3. Laurence & Bennett, Clinical Pharmacology 6th ed (1987)