pharmacology of Histamines , Serotonin and its antagonist

Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Histamine is involved in the inflammatory response and has a central role as a mediator of itching

1. (B.PHARMACY) 5th Semester Presented by Ibrahim Mussa HISTAMINE, SEROTONIN AND THEIR ANTAGONIST Submitted to: Ms . Mandeep Kaur

2. CONTENTS AUTACOID CLASSICAL AUTACOIDS HISTAMINE RECEPTORS: DISTRIBUTION AND FUNCTION PHARMACOLOGICAL ACTIONS SEROTONIN H1 ANTAGONISTS PHARMACOLOGICAL ACTIONS OF SEROTONIN 5-HT RECEPTORS 5-HT RECEPTOR ANTAGONISTS

3. Amine autacoids. Histamine, 5-Hydroxytryp- tamine (Serotonin) Lipid derived autacoids Prostaglandins, Leukotrienes , Platelet activating factor Peptide autacoids Plasma kinins ( Bradykinin , Kallidin ), Angiotensin CLASSICAL AUTACOIDS This term is derived from Greek: autos—self, akos — healing substance or remedy. Autacoid

4. Histamine and 5-Hydroxytryptamine (Serotonin)

5. Histamine Histamine  is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus.  Histamine  is involved in the inflammatory response and has a central role as a mediator of itching

6. Present almost and stored in ; mast cell Tissues rice in histamine are skin gastric mucosa and intestinal mucosa, lungs, liver and placenta. Non mast cell histamine occurs in brain , epidermis, gastric mucosa and growing regions Also presents in body secretions, venoms and pathological fluids WHERE CAN BE FOUND

7. 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

8. HOW ALLERGIC REACTION OCCUR

9. H1 – Smooth muscle, endothelium, CNS. Bronchoconstriction , vasodilation , separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness. H2 – gastric parietal cell, Regulate gastric acid secretion, vasodilation , inhibition of IgE -dependent degranulation . H3 - CNS cells, and some in peripheral NS. Presynaptic , They also control release of DA, GABA, ACh , 5-HT & NE H4 - Highly expressed in bone morrow and white blood cells. Receptors: Distribution and Function

10. Blood vessels: Dilates arterioles, capillaries, venules , IV injection- decreased BP Intradermal - Triple response Red spot (dilatation) Wheal (exudation of fluids) Flare(Reflex arteriolar dilatation) PHARMACOLOGICAL ACTIONS

11. Heart H 1 - decreased AV conduction H 2 - increased chronotropy , decreased inotropy (speed of contraction of muscles) H 1 , H 2 - increased automaticity Lung H 1 – bronchoconstriction , increased mucus viscosity H 2 - slight bronchodilation , increased mucus secretion H 1 - stimulation of vagal sensory nerve endings: cough

12. Gastrointestinal System H 2 - acid, fluid and pepsin secretion H 1 - increased intestinal motility and secretions Cutaneous Nerve Endings H 1 - pain and itching Glands Histamine causes marked increase in gastric secretion

13. PATHOPHYSIOLOGICAL ROLES 1. Gastric secretion Non mast cell histamine occurs in gastric mucosa, possibly in cells called ‘ histaminocytes ’ situated close to the parietal cells. 2. Allergic phenomena Mediation of hyper- sensitivity reactions was the first role ascribed to histamine. 3. As transmitter. Histamine is believed to be the afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings. 4. Inflammation Histamine is a mediator of vasodilatation and other changes that occur during inflammation

14. Tissue growth and repair Because growing and regenerating tissues contain high concentrations of histamine,

15. H1 ANTAGONISTS These drugs competitively antagonize actions of histamine at the H1 receptors. PHARMACOLOGICAL ACTIONS 1. Antagonism of histamine They effectively block histamine induced broncho constriction, contraction of intestinal and other smooth muscle and triple response—especially wheal, flare and itch

16. 2. Anti-allergic action Urticaria , itching and angioedema are well controlled. Anaphylactic fall in BP is only partially prevented. 3. CNS The older antihistamines produce variable degree of CNS depression. This appears to depend on the compound’s ability to penetrate 4. BP Most anti- histaminics cause a fall in BP on i.v injection

17. 5. Local anaesthetic Some drugs like pheniramine , promethazine , diphenhydramine have strong while others have weak membrane stabilizing property. However, they are not used clinically as local anaesthetic because they cause irritation when injected s.c .

18. SECOND GENERATION ANTIHISTAMINICS Loratadine Is a long-acting selective peripheral H1 antagonist which lacks CNS depressant effects and is fast acting . Levocetirizine is the active R(–) enantiomer of cetirizine . It is effective at half the dose and appears to produce less sedation and other side effects.

19.   Is an antihistamine, its principal effects are mediated via selective inhibition of peripheral H1 receptors. Cetrizine  is Used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes/nose, sneezing, hives, and itching . It works by blocking a certain natural substance (histamine) that your body makes during an allergic reaction. It also have sedative effect. It may induce sleep CETRIZINE

20. USES OF H1 ANTAGONIST Pruritides Allergic disorders Common cold : cetrizine Motion sickness: Promethzine Vertigo: Cinnarizine Cough : chlorpheniramine , diphenhydramine sedative, hypnotic, anxiolytic

21. 5-Hydroxytryptamine, its Antagonists

22. Serotonin is a naturally occurring amine synthesized from the tryptophan & commonly found in plants ,some fruits ,animal tissues & insect venoms . In human being , it is found in enterochromaffin cells in of GIT & CNS . Serotonin containing neurons are mainly found in, cortex, hypothalamus , mid –brain, vomiting centre & spinal cord . These regulate sleep, body temperature & mood . A hormone melatonin is derived from serotonin . SEROTONIN

23. PHARMACOLOGICAL ACTIONS OF SEROTONIN • Action on GIT 5-HT act as a local hormone & to regulate peristalsis movement. • Action on CNS It act as neurotransmitter in CNS Action on CVS 5-HT produces positive ionotropic EFFECT & chromotropic effect in myocardium . Action on smooth muscles 5-HT constrict the smooth muscles of bronchia and GIT .

24. Action on blood vessels 5-HT dilate the blood vessels of skeletal muscles, coronary arteries & capillary of skin . Action on platelets It enhance the aggregation of platelets & haemostatis .

25. The 5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand . 5-HT RECEPTORS

26. TYPES 5-HT1-receptors :occur mainly in CNS and some blood vessels Effects are neural inhibition and vasoconstriction. Act by inhibiting adenylate cyclase . 5-HT2-receptors : it occur in CNS and many peripheral sites (especially blood vessels, platelets, autonomic neurons). it has Neuronal and smooth muscle effects are excitatory. 5-HT 3 receptors: It occur in peripheral nervous system and in CNS. Effects are excitatory, mediated via direct receptor-coupled ion channel.

27. 5-HT 4 -receptors , it occur mainly in the enteric nervous system also in CNS. Effects are excitatory, causing increased gastrointestinal motility. Act by stimulating adenylate cyclase

28. PATHOPHYSIOLOGICAL ROLES Neurotransmitter Precursor of melatonin Neuroendocrine functions Nausea and vomiting Migraine Haemostasis Hypertension Intestinal motility

29. DRUGS AFFECTING 5-HT SYSTEM 5-HT PRECURSORS: Tryptophan increase brain 5-HT & produce behavioral effects. SYNTHESIS INHIBITORS p- Chlorophenylalanin selectively inhibit tryptophan hydroxylase & reduce 5-HT level in tissue . UPTAKE INHIBITORS Tricyclic antidepressants inhibit 5-HT uptake along with NA .Some like fluoxetine , sertraline are selective serotonin reuptake inhibitors. STORAGE INHIBITORS Reserpine block 5-HT uptake into storage granules & cause depletion of all cell monoamines .

30. DEGRADATION INHIBITORS Non-selective MAO inhibitors: tranylcypromine selective MAO –A inhibitors ( chlorgyline ) increase 5-HT content by preventing its degradation. NEURONAL DEGENERATION 5,6-Dihydroxytryptamine selectively destroys 5-HT neurons .

31. 5 -HT RECEPTOR ANTAGONISTS Cyproheptadine Methysergide Ketanserin Clozapine Risperidone Ondansetron

32. CYPROHEPTADINE Cy proheptadine  is an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes/nose, sneezing, hives, and itching. It works by blocking a certain natural substance (histamine) that your body makes during an allergic reaction Side effects: drowsiness, dry mouth , confusion.

33. METHYSERGIDE Antagonize action of 5-HT on smooth muscles including that of blood Used for migraine prophylaxis ONDANSETRON Selectively 5-HT 3 Antagonist Remarkable efficacy in controlling nausea & vomiting following administration of highly emetic anticancer drugs & radiotherapy

34. KETANSERIN Selective 5HT 2 receptor blocking property with action on 5HT 1 ,5HT3 & 5HT 4 receptors . 5HT induced vasoconstriction ,platelets aggregation & contraction of airway smooth muscles are antagonized but not contraction of guinea pig ileum or rat stomach

35. Clozapine In addition to being a dopaminergic antagonist (weaker than the typical neuroleptics ) , this atypical antipsychotic is a 5-HT2 blocker. Clozapine may also exert inverse agonist activity at cerebral 5-HT2 receptors which may account for its efficacy in resistant cases of schizophrenia. 39

36. REFERENCE Goodman & Gilman’s “ The Pharmacological basis of Therapeutics ” Eleventh Edition, 2001. Published By McGraw- Hill Publishing Company. “ Tripathi K D”; “ Essential of Medical Pharmacology ”; Fifth edition 2003, Published by Jaypee Brothers .

37. THANK YOU FOR YOUR ATTENTION