Histamine and antihistamine drugs

Pharmacotherapy of Histamine, antihistamine drugs and serotonin (5HT) Drugs.

1. A u tac o ids & serotonin By Dr. Manoj Kumar Assistant Professor Department of Pharmacology Adesh Medical College & Hospital Ambala Can’t

2. A u tac o ids Greek: autos – self and akos – Remedy or healing substance. Biological agents Act locally (e.g . within inflammatory pockets) at the site of synthesis and release. Generally act locally also called “local hormones”( short action) Amine Autacoids: Histamine and Serotonin Lipid derived: PG, LT and PAF Peptides: Plasma kinins and Angiotensin

3. Histamine - Introduction Meaning “tissue amine” ( histos – tissue) Physiological and Pathological role hypersensitivity & tissue injury The primary site, mast cell granules (or basophiles) – skin, intestinal, gastric mucosa, lungs, liver and placenta Other sites CNS: neurotransmitter Funds of the stomach: major acid secretagogues epidermis, gastric mucosa, growing regions, poison.

4. Synthesis & metabolism of histamine Synthesized by decarboxylation of amino acid histidine

5. Distribution & storage : Histamine - storage granules of mast cells . Tissues rich in histamine - skin, gastric and intestinal mucosa, lungs , liver and placenta. Non - mast cell histamine occurs in brain , epidermis, gastric mucosa.

6. Releasing Agents Non-immune Releasers Morphine and other opioids Aspirin and other NSAIDs in some asthmatics Vancomycin i.v . ( Red man syndrome), polymixin B Some x-ray contrast media Succinylcholine, d- tubocurarine Anaphylotoxins: Cold or solar urticaria IgE - Mediated Releasers Food: eggs, peanuts, milk products, strawberries , grains. Drugs : penicillins, sulfonamides etc. Venoms : fire ants, snake, bee . Foreign proteins : nonhuman insulin, serum proteins . Enzymes : C hymopapain

7. Classification • • 1 st Generation : H1 ANTAGONIST Highly sedatives: Diphenhydramine , Promethazine and Hydroxyzine Moderately sedatives : Pheniramine, Cyproheptadine, Meclizine, Buclizine and Cinnarizine Mild sedatives : Chlorpheniramine, Dexchlorpheniramine, Dimethindene, Cyclizine, Clemastine 2 nd Generation : Fexofenadine , Loratidine , Cetirizine , Levocetrizine, Azelastine, Mizolastine , Desloratidine , Ebastine and Rupatidine

8. PATHOPHYSIOLOGICAL ROLES 1. Gastric secretion Histamine - ↑ secretion of HCl (Acid and pepsin ) i n the stomach It is released – feeding , vagal stimulation. Act on H2 receptor stimulate parental cell. 2. Allergic phenomenon 3. Transmitter - start the sensation of itch and pain at sensory nerve endings. 4. Inflammation -Histamine is a mediator of vasodilatation 5. Tissue growth and repair. 6. Headache

9. Exocrine Glands Salivary glands Sweat glands Pancreas Bronchial glands Lachrymal glands Gastric glands ↑ Secretion

10. 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 Larger arteries and veins – constriction mediated by H 1 receptor Increased capillary permeability – exudation of plasma

11. Triple Response Intra dermal histamine injection causes: Red spot (few mm) in seconds: direct vasodilation effect , H1 receptor mediated Flare (1cm beyond site): axonal reflexes, indirect vasodilation , and itching, H1 receptor mediated 3. Wheal (1-2 min) same area as original spot, o edema due to increased capillary permeability H1 receptor mediated

12. Heart Direct effects of histamine are not prominent, but the isolated heart, especially of guinea pig, is stimulated—rate as well as force of contraction. These are primarily H2 responses. Visceral smooth muscles: Bronchoconstriction, intestinal contractions increased (colic), Uterus not affected

13. Sensory Nerve endings: Itching on injected , High doses – pain Autonomic ganglia and Adrenal Medulla : Adrenaline release – rise in BP CNS: IV injection Does not cross BBB – no CNS effects intracerebral injection: Rise in BP, Cardiac stimulation, hypothermia, vomiting

14. General Mechanism of Action of Antihistamines Blocks action of histamine at receptor Competes with histamine binding Displaces histamine from receptor Most beneficial when given early

15. Pharmacological actions Antagonism of Histamine: The block bronchoconstriction, contraction of intestinal and other smooth muscles and triple response Low dose BP fall antagonized Constriction of large vessels also antagonized Gastric secretion – unchanged Antiallergic action : Type 1 hypersensitivity reactions – suppressed Urticaria, itching, angioedema – controlled Anaphylactic fall in BP – partially prevented Asthma in human – not affected

16. CNS: CNS depression (sedation ) , dizziness , decrees concentration depends on individual drugs – ability to cross BBB Promethazine C ontrols motion sickness and vomiting of pregnancy C ontrols rigidity and tremor in Parkinsonism

17. . Anticholinergic : Anticholinergic properties – Promethazine highest – additive action with Atropine , TCAs etc. Local anaesthetic: Pheniramine – membrane stabilizing effects – LA – but not used BP: Fall in BP with IV injection (all) but not with Oral

18. Pharmacokinetics L ipid 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 excreted mainly unmetabolized form C and L are primarily excreted in the urine F is primarily excreted in the feces

19. Clinical Uses of Antihistamines Allergic rhinitis (common cold) Allergic conjunctivitis (pink eye) Allergic dermatological conditions Urticaria (hives) Angioedema (swelling of lips-eyelids ) Puritus (atopic dermatitis, insect bites) Anaphylactic reactions (severe allergies ) Seasonal Hay fever Nausea and vomiting (first generation H 1 - antihistamines) Sedation (first generation H 1 -antihistamines)

20. 2 nd Generation antihistaminics • ( SGAs) – after 1980s Higher affinity for H 1 receptors: no anticholinergic side effects No CNS depressant property Additional antiallergic – LT and PAF inhibition Advantages over 1 st generation: No psychomotor impairment – driving etc. can be allowed No subjective effect No sleep induction Do not potentiate BDZ and alcohol etc.

21. Fexofenadine : First non-sedating SGA - when co-administered with CYP3A4 inhibitors – erythromycin, clarithromycin , ketoconazole and itraconazole etc Terfenadine , Astimazole etc. – banned

22. Loratidine : Long acting, selective peripheral H1 blocker – fast acting and lacks CNS depression – metabolized by CYP3A4 No interaction with macrolides and no arrhythmias Uses: Urticaria and atopic dermatitis. Desloratidine : Metabolite like Loratidine – with its double potency

23. Cetirizine : Most commonly used( Levocetirizine – same with lesser S/E ) High affinity for Peripheral H1 receptor, but poor cross BBB at high dose Not metabolized in body , no cardiac action . Other anti-allergic action – inhibits histamine and cytotoxic material release f or platelets and eosinophils High skin concentration – beneficial urticaria and atopic dermatitis Longer half life 7-10 hr – once daily dosing Uses: Upper respiratory allergies, pollinosis, urticaria and atopic dermatitis and seasonal asthma

24. Azelastine : H 1 blocker with topical action – also inhibitor of inflammatory response mediated by LT and PAF. Nasal mucosa – Intranasal application - Half-life 24 hours but action longer due to active metabolites Used intranasal in seasonal and perennial rhinitis Mizolastine : Non-sedating – effective in rhinitis and urticaria . – 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

25. Adverse effects F irst generation H 1 -antihistamines Side effects are due to CNS depression : Sedation Dizziness Tinnitus (ringing in the ear) Blurred vision Euphoria Uncoordination Anxiety Insomnia Tremor Nausea/vomitting Dry mouth/dry cough S econd generation H1-antihistamines side effects (drowsiness, fatigue, headache, nausea and dry mouth)

26. H 2 - r ec e p t or antag o ni sts Cimetidine, Ranitidine, Famotidine and Roxatidine ……. ….. “ Drugs for Peptic Ulcer ”

27. Serotonin and Anti-serotonin drugs

28. Serotonin Monoamine neurotransmitter Synthesized from tryptophan 90 % present in gastro-intestinal enterochromaffin cells and 10 % in platelets and brain. Role in mood, sleep, sexual activity, thermoregulation, pain .

29. Biosynthesis Tryptophan ( From diet) Tryptophan hydroxylase 5Hydroxytryptophan Aromatic Amino Acid decardoxylase 5-Hydroxy tryptamine Monoamine oxidase(MAO) 5 Hydroxyindole acetaldehyde Aldehyde dehydrogenase 5Hydroxyindole acetic acid (5HIAA)

30. Storage and release

31. Distribution GIT enterochromaffin cells (90%)and myentric plexus. Platelets Lungs B one marrow P ineal gland CNS

32. Serotonin Receptors seven main types ( 5-HT 1 to 5-HT 7 ). 5-HT 1 , 5-HT 2 subdivided Total 14 types of 5-HT receptors present . Different monoamine transporters Dopamine transporter Norepinephrine transporter Serotonin transporter

33. A gents can inhibit 5-HT reuptake • • • Cocaine Tricyclic antidepressants Selective serotonin reuptake inhibitors(SSRIs) e.g. Fluoxetine

34. Elimination Metabolized by MAO and then Aldehyde dehydrogenase to form 5-hydroxyindole acetic acid(5-HIAA) E xcreted in urine

35. CNS – As Neurotransmitter Behavioral responses Feeding behavior Mood and emotion control Sleep / wakefulness control Emetic reflex (esp. chemical triggered) Control of sensory pathways Pharmacological Actions

36. Pharmacological Actions CVS Contraction of vascular smooth muscle except in skeletal muscle and heart IV injection causes triple response BP Triphasic response : fall – Coronary chemoreflex rise – Vasoconstriction,↑co fall - Vasodilation in skeletal M.& arterioles

37. GIT Stimulates peristalsis ↑ mucus production ↓acid and pepsin Others Stimulates perception of pain and itch by activating 5HT 3 receptors ↓ food intake Bronchi - Bronchoconstriction (5HT 2A ) Platelets – platelet aggregation (5HT 2A ) Pharmacological Actions

38. 5 HT receptor agonists Buspirone: 5HT 1A used in anxiety Sumatriptan: 5HT 1 B/D used in migraine Cisapride, mosapride: 5 HT 4 used in GERD Dexfenfluramine: Non selective 5HT 2 Agonist (BANNED) Lorcaserin: 5HT 2C used in obesity

39. 5 HT receptor antagonists Cyproheptadine: 5 HT 2A Methysergide: 5HT 2A/2C Ketanserin: 5HT 2A/2C Clozapine: 5HT 2A/2C (D 2 to lesser extent) Risperidone : 5HT 2A + D 2 antagonist Ondansetron: 5 HT 3 antagonist

40. Cisapride Has peripheral 5HT 4 agonist action Useful in GERD, Diabetic gastroparesis Releases Ach from cholinergic neurones in myenteric plexus Oral bioavailabilty ~30% T ½ 10 hrs Reported to cause serious ventricular arrhythmias Others are Renzapride, Mosapride

41. A llergies A ppetite stimulant S erotonin syndrome C arcinoid syndrome P riapism Adverse effects: Dryness of mouth, W eight gain, D rowsiness Used

42. Sumatriptan Selective agonist for 5HT 1D and 5HT 1B Useful in acute migraine attack Bioavailability ~ 15% Half life 2-3 hrs Can be given orally, S/C or as nasal spray Can cause chest pain in 5% patients Zolmitriptan, Naratriptan can be given orally, longer acting, safer

43. Buspirone Partial agonist at presynaptic 5HT 1A receptors Weak D 2 blocker Useful as anxiolytic Rapidly absorbed , undergoes extensive first pass metabolism t ½ 2-4 hrs Excreted in urine and faeces

44. Ketanserin Selective 5HT 2 blocker No partial agonistic activity Weak α 1 , H 1 , Dopaminergic blocker Useful in Raynaud’s diasease Has antihypertensive activity Congener is Ritanserin more selective for 5HT 2A

45. Cyproheptadine 5HT 2A antagonist Has additional H 1 blocking as well as anticholinergic activity Useful in Carcinoid tumor Post-gastrectomy dumping syndrome Pruritis All e r g i e s ↑Appetite in children

46. Ondansetron Selective 5HT 3 antagonist Useful as antiemetic agent Others are G r an i se t r o n Tropisetron

47. M et h y s ergid e Chemically related to ergot alkaloids Potent 5HT 2 A / 2 C antagonist Acts on 5HT 1 receptors also Useful in Migraine prophylaxis Carcinoid tumor Post-gastrectomy dumping syndrome Prolonged use in endocardial, pulmonary fibrosis

48. Ergot alkaloids Natural ergot alkaloids Ergometrine Ergotamine Synthetic Dihydroergotamine Dihydroergotoxine Bromocriptine

49. Ergot related drugs Ergotamine : Partial agonist & antagonist at , 5 HT 1 & 5 HT 2 receptors Produces sustained vasoconstriction , visceral smooth muscle contraction , vasomotor centre depression Chronic exposure can cause gangrene Bromocriptine: D 2 agonist inhibits prolactin release Ergometrine: – Oxytocic drug

50. Ergot related drugs Adverse events : Nausea, vomiting abdominal pain , muscle cramps weakness, paresthesia Chest pain coronary artery & other vascular spasm Contraindications: Sepsis, IHD, PVD, Pregnancy, liver & kidney disease

51. Serotonergic drugs: actions & uses Sr. no Receptor Drug action Drug example Clinical disorder 1. 5HT 1A partial agonist B u s p i r on e , ipsapirone Anxiety, Dep r e s sion 2. 5 HT 1B/1D Agonist Sumatriptan Migraine 3. 5 HT 2A/2C Antagonists M e t h y s e r gide, Trazadone, Risperidone, ketanserin Migraine Depression Sch i z oph r e n i a 4. 5 HT 3 Antagonists Ondansetron Chemotherapy , radiotherapy induced emesis 5. 5 HT4 Agonists C i s a pr i d e , t e g ase r od GIT disorders

52. Migraine

53. What is Migraine? Repeated attacks of headache Moderately or severely painful Frequent or infrequent Last a few hours to a couple of days Often only one side of the head hurts

54. What You Might Experience During an Attack Nausea Vomiting Diarrhea Sweating Cold hands Sensitivity to light Sensitivity to sound Scalp tenderness Pressure pain

55. Triggers: Changes in Daily Cycles

56. Triggers: Environment or Diet

57. Triggers: Mental

58. Drugs for Migraine Mild Migraine (NSAIDS and antiemetics) Ibuprofen 400 mg TDS Paracetamol 500 mg TDS Naproxen 500 mg TDS Antiemetics: Metoclopramide 10 mg oral/ Domperidone 10 mg Oral Moderate migraine N S AIDS c ombin a tion / tri p t ans li k e sum a tri p t an + antiemetic Severe : triptans/ ergotamine + Prophylaxis + antiemetic

59. Prophylaxis of migraine Necessary when attacks are frequent ( 2 or more attacks per month ) Discontinue every 4-6 months and observe Drugs for prophylaxis of migraine Propranolol 40 mg BD Amitryptilline 25 mg BD Flunnarizine Valproic acid, gabapentin , topiramate (Anti-epileptics)

60. Sumatriptan Selective 5HT 1B/1D receptor agonist Constriction of dilated extracerebral blood vessels Inhibition of release of 5HT and inflammatory neuropeptides around the affected vessels Supression of neurogenic inflammation Dose: 50 -100 mg

61. Sumatriptan Adverse effects Dose related: Tightness of chest, feeling of heat, paresthesias, dizziness, weakness Risk of Myocardial infarction, seizure and death Contraindications: Ischemic heart disease, epilepsy, hypertension, pregnancy, hepatic and renal imairment Other triptans: Rizatriptan, zolmitriptan, naratriptan, almotriptan

62. Case study A 2 8 -year-old male, Ajay Kumar develops a runny nose, itchy eyes, and sneezing every winter. To relieve his symptoms, he takes an OTC antihistamine Ajay Kumar is annoyed by the unpleasant effects that accompany his allergy medication. Every time he takes this 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.

63. Questions What Is Ajay Kumar Problem ? Which OTC is probably Ajay Kumar taking? What is the reason of drowsiness and dryness of mouth in Ajay Kumar ? What is loratadine ? Why did Physician prescribe it for Ajay Kumar ?