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Histamine and antihistaminics
Dr. D.K. Brahma discusses autacoids, focusing on histamine and its physiological and pharmacological roles. Histamine is involved in various bodily functions, including allergic responses and gastric secretion, with distinct pathways for synthesis, release, and pharmacological action through H1 and H2 receptors. The document also outlines the classifications, actions, and therapeutic uses of both first and second-generation antihistamines.
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Introduction of Dr. D. K. Brahma, Associate Professor of Pharmacology at NEIGRIHMS.
Definition of Autacoids, their diverse sources, and examples: amine autacoids and lipid-derived substances.
Introduction to Histamine, its roles as a mediator in hypersensitivity and locations within the body.
Explanation of Histamine synthesis from histidine, storage in mast cells, and its metabolic pathways.
Details on H1, H2, and H3 histamine receptors, their selective agonists and antagonists, and physiological effects.
Mechanisms of histamine release, including IgE-mediated and non-immune pathways, along with examples.
Histamine's effects on blood vessels, including vasodilation and increased permeability through receptors.
Description of the triple response to subdermal histamine injection: red spot, flare, and wheal.
Impact of histamine on cardiac contractility and rhythm, effects via H1 and H2 receptors.
Histamine's role in smooth muscle reactions, glandular secretion, and effects on the CNS.
Gastric secretion, allergic reactions, as a transmitter, and its role in inflammation.
Classification of antihistamines as physiological and pharmacological antagonists.
Classification of first-generation and second-generation antihistamines based on sedation levels.
How antihistamines counteract effects of histamine, including allergic reactions and sedation.
Absorption, metabolism, and excretion of antihistamines, including differences in generations.
Common adverse effects of H1 antagonists including sedation, CNS effects, and overdose risks.
Uses of antihistamines in allergic conditions, motion sickness, preanesthetic medication, and more.
Advantages of second-generation antihistamines over first-generation regarding side effects.
Specific examples of second-generation antihistamines and their clinical uses and side effects.
Mention of H2-receptor antagonists, to be discussed later regarding their role in peptic ulcers.
Summary of critical points related to histamine, receptors, antihistamines, and their therapeutic uses.
Closing remarks and thanks for the presentation.
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Histamine and antihistaminics
- 1. Dr. D. K.Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
- 2. Autacoids • Greek: autos– self and akos - healing substance or remedy • Diverse substances, produced by a wide variety of cells – generally act locally • Also called local hormones – but differs from them • A number of Physiological and pathological processes and also transmitters to Nervous system • Amine Autacoids: Histamine and Serotonin • Lipid derived: PG, LT and PAF • Peptides: Plasma kinins and Angiotensin
- 3. Histamine - Introduction •Meaning “tissue amine” (histos – tissue) – abundantly present in animal tissues – also in plants like “stinging nettle” • Mediator of hypersensitivity and tissue potential tissue injury – Physiological role • The primary site the mast cell granules (or basophils) – skin, intestinal and gastric mucosa, lungs, liver and placenta • Other sites – central nervous system: neurotransmitter – the fundus of the stomach: major acid secretagogues, epidermis, gastric mucosa and growing regions – also blood, body secretions, venoms & pathological fluids
- 4. Histamine – synthesis,storage and release • Synthesized locally from amino acid histidine • Histidine L-histidine decarboxylase Histamine • Metabolized by P450 system, 2 pathways: – Methylation to N-me histamine (N-me transferase), and to N-me imidazole acetic acid (MAO) - eliminated in urine – Oxidative deamination to imidazole acetic acid (DAO), and to imidazole acetic acid riboside - eliminated in urine • In mast cells – held by acidic protein and heparin (-ve charged) – histamine is +ve charged • Ineffective orally – liver destroys all absorbed from intestine
- 5. Histamine Receptors H1 H2H3 Selective agonist 2-Methylhistamine 4-Methylhistamine α-Methylhistamine Selective antagonist Mepyramine Cimetidine Ranitidine Thioperamide Effector Pathway IP3/DAG cAMP Ca++ influx K+ channel activation Distribution •Smooth muscle (intestine, airway, uterus •Blood vessels – NO and PGI2 release – Vasodilatation and also vasoconstriction • Afferent nerves – stimulation •Ganglion cells – stimulation •Adrenal medulla – CA release •Brain - transmitter •Gastric glands – acid secretion •Blood vessels – dilatation •Heart: Atria: + chronotropy and ventricles: + inotropy •Uterus – relaxation •Brain - transmitter •Brain – inhibition oh Histamine release •Lung, spleen, gatric mucosa – decrease release •Ileum – inhibition of Ach release •Cerebral vessels – NA release inhibition
- 6. HA HA HA HA HA HA Y YNon-immune Releasers (opioids, tubocurarine, vancomycin etc) IgE ANTIGEN PGs & LTs PROTEASES HISTAMINE OTHER MEDIATORS (PAF,TNF,ILs) IgE - Antibody Induced Release (food, penicillin, venoms, etc) ACUTE INFLAMMATORY RESPONSE - IMMEDIATE HYPERSENSITIVITY REACTION Inhibitors of Release (Cromolyn, Albuterol) HA Fc€RI Prot + Hista Or Hep + Hist Hist Na+ or Ca++ t-pr-K PIP2 IP3 Ca++
- 7. Releasing Agents IgE -Mediated Releasers • Food: eggs, peanuts, milk products, grains, strawberries, etc • Drugs: penicillins, sulfonamides, etc • Venoms: fire ants, snake, bee, etc • Foreign proteins: nonhuman insulin, serum proteins, etc • Enzymes: chymopapain Non-immune Releasers • Morphine and other opioids, i.v. • Aspirin and other NSAIDs in some asthmatics • Vancomycin, i.v. (Red man syndrome), polymixin B • Some x-ray contrast media • Succinylcholine, d- tubocurarine • Anaphylotoxins: c3a, c5a • Cold or solar urticaria
- 8. Histamine - Pharmacological actions •Blood vessels: Dilatation of small vessels – arterioles, capillaries and venules – SC administration – flushing, heat, increased HR and CO – little fall in BP – Rapid IV injection: Fall in BP early (H1) and persistent (H2) – only H1 effect with low dose – Dilatation of cranial vessels – H1 component vasodilatation – mediated indirectly by EDRF .. But H2 component - mediation is directly on smooth muscle of blood vessels – Larger arteries and veins – constriction mediated by H1 receptor – Increased capillary permeability – exudation of plasma
- 9. Histamine – The TripleResponse Subdermal histamine injection causes: 1. Red spot (few mm) in seconds: direct vasodilation effect , H1 receptor mediated 2. Flare (1cm beyond site): axonal reflexes, indirect vasodilation, and itching, H1 receptor mediated 3. Wheal (1-2 min) same area as original spot, edema due to increased capillary permeability, H1 receptor mediated
- 10. Pharmacological actions -Heart • Affects both cardiac contractility and electrical events directly – It increases the force of contraction of both atrial and ventricular muscle by promoting the influx of Ca2+, and • Increased heart rate by hastening diastolic depolarization in the sinoatrial (SA) node • It also acts directly to slow atrioventricular (AV) conduction, to increase automaticity, and in high doses especially - to elicit arrhythmias. • With the exception of slowed AV conduction, which involves mainly H1 receptors ----- all these effects are largely attributable to H2 receptors and cAMP accumulation • If histamine is given i.v., direct cardiac effects of histamine are overshadowed by baroreceptor reflexes elicited by the reduced blood pressure • Overall: H1 – decreased AV conduction; H2 - Increased Chronotropy and automaticity
- 11. Pharmacological actions –contd. • Visceral smooth muscles: Bronchoconstriction, intestinal contractions increased (colic), Uterus not affected • Glands: Gastric secretion (also pepsin) – H2 receptor mediated – cAMP generation and proton pump activation • Sensory Nerve endings: Itching on injected; High doses – pain • Autonomic ganglia and Adrenal Medulla: Adrenaline release – rise in BP • CNS: Does not cross BBB – no CNS effects on IV – intracerebral injection: Rise in BP, Cardiac stimulation, hypothermia, arousal, vomiting
- 12. Histamine - Pathophysiological RolesGastric Secretion: Dominant Physiological Role – Non-mast cell histamines – Gastric mucosa • All components involve to release it – feeding, vagal, cholinergic and gastrin • H2 blockers – Suppress the release – antimuscarinics reduce the effects of Histamine • Allergic Phenomena: First Role – mediation of hypersensitivity reactions • AG:AB reactions released by mast cells involving IgE types • Urticaria, angioedema, brochoconstriction and anaphylactic reaction • Antihistaminics – counter above effects except Brochial asthma Transmitter: Afferent transmitter – itch and pain • Non-mast cell histamines - maintain wakefulness (midbrain and hypothalumus) .. antihistaminics cause sedation) …. also suppress appetite, regulates body temperature, thirst and hormone release from anterior pituitary Inflammation: Vasodilatation in inflammation and adhesion of leucocytes
- 13. Histamine H1-receptor antagonists •Physiological antagonism (e.g., epinephrine) • Inhibit the release of histamine (e.g., cromolyn • Pharmacological antagonism (antihistamines) First Generation: Sedating Second Generation: Nonsedating
- 14. Classification • 1st Generation: – Highlysedatives: Diphenhydramine, Dimenhydrate, Promethazine and Hydroxyzine – Moderately: Pheniramine, Cyproheptadine, Meclizine, Buclizine and Cinnarizine – Mild: Chlorpheniramine, Dexchlorpheniramine, Dimethindene, Cyclizine, Clemastine • 2nd Generation: Fexofenadine, Loratidine, Desloratidine, Cetirizine, Levocetrizine, Azelastine, Mizolastine, Ebastine and Rupatidine
- 15. Antihistaminics – Pharmacological actions •Antagonism of Histamine: – Effectively block bronchoconstriction, contraction of intestinal and other smooth muscles and triple response – Low dose BP fall antagonized, but needs H2 blockers to counter high dose fall in BP – Constriction of large vessels also antagonized – Gastric secretion – unchanged • Antiallergic action: Manifestations of Type 1 hypersensitivity reactions – suppressed – Urticaria, itching, angioedema – controlled – Anaphylactic fall in BP – partially prevented – Asthma in human – not affected (other mediators)
- 16. Antihistaminics – Pharmacological actions……. contd. • CNS: Variable degree of CNS depression (sedation)– depends on individual drugs – ability to cross BBB and CNS:Peripheral H1 receptor affinity – Inter-individual variation – Some Individuals: stimulant effects – restlessness and Insomnia etc. – 2nd generation – Non-sedating – Promethazine – controls motion sickness (unknown mechanism) and vomiting of pregnancy – Promethazine – controls rigidity and tremor in Parkinsonism • Anticholinergic: Many are anticholinergic properties – Promethazine highest – additive action with Atropine, TCAs etc. • Local anaesthetic: Pheniramine – membrane stabilizing effects – LA – but not used (Irritation) – also antiarrhytmic • BP: Fall in BP with IV injection (all) but not with Oral
- 17. Pharmacokinetics • Classically –lipid soluble, well absorbed orally and parenterally, metabolized in Liver and excreted in urine – Widely distributed in body and enters Brain and crosses BBB – Induce microsomal hepatic enzyme – Duration of action 4-6 Hours except ….. – Cetirizine (C), loratadine (L), fexofenadine (F) - well absorbed and are excreted mainly unmetabolized form – C and L are primarily excreted in the urine – F is primarily excreted in the feces
- 18. ADRs - H1- antgonists • Frequent but mild – inter-individual difference to different drugs – Sedation (Paradoxical Excitation in children), diminished alertness, loss to concentrate, dizziness, motor incordination, tendency to fall asleep – commonest – say no to motor vehicle driving and operation – Alcohol synergises CNS effects – Tachydysrhythmias in overdose - rare • Allergic reactions with topical use (contact dermatitis) • Peripheral antimuscarinic effects – Dryness of mouth, blurred Vision, constipation, urinary retention – Epigastric distress and headache • Acute overdose: CNS excitation, tremor hallucinations – resemble Atropine poisoning - death due to respiratory failure and CVS failure
- 19. Therapeutic uses • Allergicreactions: Does not suppress AG:AB reaction – but blocks release of histamine – palliative – Itching, urticaria, seasonal hay fever, allergic conjunctivitis, angioedema of lips-eyelids etc. --- Laryngeal angioedema (Adrenaline) – Anaphylactic shock - cannot be relied – Less effective in perennial vasomotor rhinitis, atopic dermatitis, and chronic dermatitis – H2 antagonist combination – Bronchial asthma – no use – 1) other mediators than histamine 2) concentration at the site may not be sufficient – Not effective in humoral and cell mediated allergies • Other conditions : (histamine) – Insect bite, Ivy poisoning – symptomatic relief • Prunitides: Antipruritic - Independent of antihistaminic action • Common cold: Symptomatic relief – older ones preferred
- 20. Antihistaminics - Therapeuticuses – contd. • Motion Sickness: Promethazine, diphenhydramine, dimenhydrinate and cyclizine – 1 hour befor journey – Promethazine – morning sickness, drug induced and post operative vomiting and radiation vomiting • Vertigo: Cinnarizine • Preanaesthetic medication • Cough: Chlorpheniraine maleate, diphenhydramine, promethazine etc. • Parkinsonism: Promethazine – anticholinergic and sedative • Acute muscular dystonia: Parenteral Promethazine – anti-dopamineric and antipsychotic drugs • Sedative-hypnotic: Promethazine – respiratory depression (not below 2 years) – not preferred ……. Hydroxyzine
- 21. 2nd Generation antihistaminics • 2nd generation(SGAs) – after 1980s – Higher affinity for H1 receptors: no anticholinergic side effects – Absence of CNS depressant property – Additional antiallergic – LT and PAF inhibition • Advantages over 1st generation: – No psychomotor impairment – driving etc. can be allowed – No subjective effect – No sleep induction – Do not potentiate BDZ and alcohol etc.
- 22. Individual Antihistaminics 2nd Generation: ingeneral, these agents have a much lower incidence of adverse effects than the first generation agents • Fexofenadine: First non-sedating SGA - banned – Torades de pointes … when co-administered with CYP3A4 inhibitors – erythromycin, clarithromycin, ketoconazole and itraconazole etc. – Blocking of delayed rectifier K+ channel in Heart at high doses – Terfenadine, Astimazole etc. – banned • Loratidine: Long acting, selective peripheral H1 blocker – fast acting and lacks CNS depression – metabolized by CYP3A4 (to an active metabolite) – No interaction with macrolides and no arrhythmias – Uses: Urticaria and atopic dermatitis • Desloratidine: Metabolite of Loratidine – with its double potency
- 23. Individual Antihistaminics –contd. • Cetirizine: Most commonly used these days (Levocetirizine – same with lesser side effects) – High affinity for Peripheral H1 receptor, but poor BBB cross, but somnolence at high dose – Not metabolized in body, no cardiac action when given with macrolides etc. – Other anti-allergic action – inhibits histamine and cytotoxic material release fro platelets and eosinophils – High skin concentration – beneficial urticaria and atopic dermatitis – Longer half life – once daily dosing – Uses: Upper respiratory allergies, pollinosis, urticaria and atopic dermatitis and seasonal asthma
- 24. Individual Antihistaminics –contd. • Azelastine: H1 blocker with topical action – also inhibitor of inflammatory response mediated by LT and PAF – Down regulation of Intracellular adhesion molecule-1 (ICAM-1) expression on nasal mucosa – Intranasal application – Half-life 24 hours but action lasts longer due to active metabolites – Used intranasal in seasonal and perennial rhinitis • Mizolastine: Non-sedating – effective in rhinitis and urticaria (no active metabolite) – Half-life 8-10 Hours but single dosing • Ebastine: Newer SGA – converts to carbastine – Half-life: 10-16 Hrs and non-sedating – Used in nasal and skin allergies – Arrhythmogenic potential
- 25. H2-receptor antagonists Cimetidine, Ranitidine,Famotidine and Roxatidine ……. ….. Will be discussed later – in “Drugs for Peptic Ulcer”
- 26. What to remember? • Histamine – Physiological Roles • Histamine receptors – locations and actions • Important antihistaminics – 1st generation and 2nd generation • 1st generation Vs 2nd generation • Uses of antihistaminics • Individual drugs – Promethazine, Fexofenadie, Cetirizine, Azelastine and Ebastine
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