Neurotransmitters and histamine pharmacology

This power point presentation deals with the different types of neurotransmitters in the CNS and and a breif information about histamine and antihistaminic drugs.

1. NEUROHUMORAL TRANSMISSION IN THE CENTRAL NERVOUS SYSTEM (CNS) AND DETAILED STUDY ABOUT THE NEUROTRANSMITTER-HISTAMINE PREPARED BY- KESHARI KUMAR SRIWASTAWA M.PHARM (PHARMACOLOGY) 1 ST YEAR

2. NEUROHUMORAL TRANSMISSION IN CNS

3. WHAT IS THE NERVOUS SYSTEM ? The system of the body that deals with the transmission and conduction of nerve impulses to and fro between different parts of the body thereby coordinating and controlling the different actions of the body is called as the nervous sytem .

4. CLASSIFICATION OF THE NERVOUS SYSTEM

5. What is Neurohumoral Transmission? It is defined as the transmission of nerve impulses from a presynaptic neuron to another postsynaptic neuron by means of humoral agents and these humoral agents are called as neurotransmitters . These humoral agents can be: (i) Biogenic amines (ii) Amino acids (iii) Peptides

6. WHAT ARE NEUROTRANSMITTERS? Neurotransmitters  are chemical messengers that transmit a message from a nerve cell across the synapse to a target cell. The target can be another nerve cell, or a muscle cell, or a gland cell. They are chemicals made by the nerve cell specifically to transmit the message.

7. NEUROTRANSMITTERS OF THE CNS There are three types of neurotransmitters present in the CNS which are : 1. Inhibitory neurotransmitters : GABA (Gamma Amino Butyric Acid) Glycine Dopamine 2. Excitatotry neurotransmitters : Glutamate Aspartate Histamine 3. Both inhibitory and excitatory eurotransmitters: A cetylcholine Noradrenaline Serotonin (5 –HT)

8. How does neurohumoral transmission occur? Neurohumoral transmission in the CNS involves 5 basic steps 1.Biosynthesis of neurotransmitters 2.Storage of neurotransmitters 3.Release of neurotransmitters 4.Interaction of neurotransmitters with specific receptors 5 Inactivation of the neurotransmitters

9. 1.BIOSYNTHESIS OF NEUROTRANSMITTERS As a rule, the synthesis of small-molecule neurotransmitters occurs within presynaptic terminals The enzymes needed for transmitter synthesis are synthesized in the neuronal cell body and transported to the nerve terminal cytoplasm at 0.5–5 millimeters a day by a mechanism called  slow axonal transport . The precursor molecules used by these synthetic enzymes are usually taken into the nerve terminal by transporter proteins found in the plasma membrane of the terminal. The enzymes generate a cytoplasmic pool of neurotransmitter that must then be loaded into synaptic vesicles by transport proteins in the vesicular membrane .

10. Schematic diagram of neuron

11. 2. STORAGE OF NEUROTRANMITTERS Neurotransmitters  are  stored  in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. The synaptic vesicles are also called as the neurotrasnmitter vesicles

12. 3. RELEASE OF NEUROTRANSMITTERS In response to a threshold action potential or graded electrical potential, a neurotransmitter is released at the presynaptic terminal. This action potential is of two types : (i) Inhibitory postsynaptic potential (IPSP) : This action potential leads to the binding and interaction of an inhibitory neurotransmitter to the specific receptors on the post junctional membrane which increases the permeabiloity of the tK + and Cl- ions (ii) Excitatory postsynaptic potential (EPSP): This action potential leads to the binding and interaction of an excitatory neurotransmitter and increases the permeability of caations like Na+ ,Ca2+ etc.

13. 4. INTERACTION OF THE NEUROTRANSMITER WITH THE RECEPTORS The released neurotransmitter may then move across the synapse to be detected by and bind with receptors in the postsynaptic neuron. The released neurotransmitters binds with the 2 types of receptors- 1. Ligand gated receptors (LGR) 2. G protein coupled receptor(GPCR) Depending upon the type of the receptor with which the neurotransmitter binds they are classifed into 2 types : (I) Fast neurotranmitters – Acting on the LGR. eg. Glutamate (ii) Slow neurotransmitters Acting on GPCR eg. Histamine Binding of neurotransmitters may influence the postsynaptic neuron in either an inhibitory or excitatory way. The binding of neurotransmitters to receptors in the postsynaptic neuron can trigger either short term changes, such as changes in the membrane potential called postsynaptic potentials, or longer term changes by the activation of signaling cascades.

14. RECEPTOR INTERACTION

15. Name of neurotransmitter Receptor with which it interacts Type of receptor GABA (Gamma aamino butyric acid) GABA A GABA B LGR GPCR GLYCINE Closely related to GABA A receptors LGR DOPAMINE D1 ,D2 ,D3,D4,D5, GPCR GLUTAMATE NMDA AMPA KAINATE LGR ASPARTATE NMDA LGR ACETYLCHOKINE MUSCARINIC NICOTINIC GPCR LGR NOR ADRENALINE α 1 α 2 β 1 GPCR SEROTONIN 5HT1,5HT2,5HT4,5HT5, 5HT6,5HT7 5HT3 GPCR LGR

16. 5. INACTIVATION OF THE NEUROTRANSMITTERS After a neurotransmitter molecule has been recognized by a post-synaptic receptor, it is released back into the synaptic cleft. Once in the synapse, it must be quickly removed or chemically inactivated in order to prevent constant stimulation of the post-synaptic cell and an excessive firing of action potentials. Some neurotransmitters are removed from the synaptic cleft by special  transporter proteins  on the pre-synaptic membrane. These transporter proteins carry the neurotransmitter back into the pre-synaptic cell, where it is either re-packaged into a vesicle and stored until it is once again needed to transmit a chemical message, or broken down by enzymes. Serotonin is one neurotransmitter that gets recycled in this way. 

17. Not all neurotransmitters are recycled by the presynaptic cell. Neuropeptide neurotransmitters merely quickly diffuse away from the receptors into the surrounding medium. One important neurotransmitter, acetylcholine, has a specialized enzyme for inactivation right in the synaptic cleft called acetylcholinesterase (AChE. AChE is an enzyme present at all cholinergic synapses which serves to inactivate acetylcholine by hydrolysis.  The inactivation of the neurotransmitter leads to the termination of its action

18. Factors regulating neurohumoral transmission . Neurohumoral transmission is regulated by several different factors: 1. the availability and rate-of-synthesis of the neurotransmitter, 2. The release of that neurotransmitter, the baseline activity of the postsynaptic cell, 3. The number of available postsynaptic receptors for the neurotransmitter to bind to, 4. The subsequent removal or deactivation of the neurotransmitter by enzymes or presynaptic reuptake .

19. MANIFESTATIONS OF CNS STIMULATION (EXCITATION) AND DEPRESSION (INHIBITION) CNS Depression CNS Stimulation Drowsiness Excitement Sedation Euphoria Hypnosis Insomnia Disorientation Tremor Confusion Twitching Unconsciousness Convulsions Coma Coma Death Death

20. PHARMACOLOGICAL STUDY OF HISTAMINE

21. WHAT IS HISTAMINE? Histamine is a biosynthetic mono amine which is also an excitatory neurotranmitter of the brain,spinal cord and uterus Histamine is also an autocoid released mainly from the granules of the mast cells and basophils of the l eukocytes . Histamine is an endogeneous substance of the body which is involved in the local immune as well as inflammatory responses of the body and is a prime mediator of itching.

22. CHEMICAL STRUCTURE OF HISTAMINE

23. SYNTHESIS OF HISTAMINE Histamine  is  synthesized  primarily by mast cells, basophils, histaminergic neurons in the basal ganglia of the brain and enterochromaffin-like cells (ECL) in the stomach . Histamine is produced by the decarboxylation of the basic amino acid histidine in the presence of the enzyme histidine decarboxylase It is a hydrophilic vasoactive amine The synthesized histamine are later on metabolized by the enzyme Histamine N-methyl transferase and diamine oxidase

24. Factors potentiating histamine release from mast cells Antigen –antibody reactions Certain foods like fish , crab etc. Bile salts Some basic drugs like morphine, d-TC,dextran ,hydralazine etc.

25. HOW DOES HISTAMINE ACT? Histamine exerts its pharmacological action by acting upon 4 receptors : H1 Increases Ca levels Gq Increases IP3/DAG H2 Increases CAMP Gs H3 Decreases CAMP Gi (autoreceptor) H4 Decreases CAMP GI All these receptors belong to the category of G protein coupled receptors (GPCR)

26. Pharmacological Actions of Histamine

27. Antihistaminics or histamine receptor blockers or histamine receptors antagonists The drugs which act by competitively blocking the histaminic receptors and show their pharmacological actions are called as antihistaminics . They are H1 Antihistaminics H2 Antihistaminics H3 Antihistaminics H4 Antihistaminics

28. H1 BLOCKERS OR H1 ANTIHISTAMINICS OR HI RECEPTOR ANTAGONISTS

29. Mechanism of action Competitively Blocks the H1 receptors. Examples : Cetrizine Fexofenadine Loratidine Rupatidine Diphenhydramine Hydroxyzine

30. 1 st generation H1 blockers Pharmacological actions CNS depression which leads to sedation, drowsiness and pshycomotor impairement Antiemetic action Local anaesthetic action Anti parkinsonism action Anticholinergic action Antiallergic action

31. 1 st generation H1 blockers Pharmacokinetics Absorption : Well absorbed orally and parentrally Distribution : widely distributed throughout the body Metabolism : Extensively in liver Elimination: Urine

32. 1 st generation H1 blockers Adverse effects Common side effects- sedation , drowsiness,,lack of concentration , fatigue,headache, incoordination Gastrointestinal side effects- Nausea,vomitting, loss of appetite and epigastric disturbances. Anticholinergic side effects : dryness of mouth , blurring of vision, constipation and urinary retention Teratogenic side effects_ are observed i some animals Allergic reactions: Rarely observed especially contact dermatitis on topical applications Terfenadine causes plymorphic ventriculatr tachycardia.

33. 1 ST generation H1 blockers Uses Allergic diseases Common cold Preanaesthetic medication Antiemetic (eg, Promethazine, diphenhydramine,dimenhydrinate are used for the prophlaxis of motion sickness) Parkinsonism ( eg. Promethazine and diphenhydramine are used for the tratment for the treatment of drug induced parkinsonism) Cinnarizine , dimenhydrinate, ,meclizine are used to control vertigo in Meniere’s disease and control other types of vertigo. Sedative and hypnotic Note The 1 st generation H1 blockers shuold not used in case of truck driver and people doing operative machinery work

34. 2 nd generation H1 blockers These drugs are highly selective for H1 receptors and possess the following properties : (i) Have no anticholinergic effect (ii) Lack antiemetic effect (iii) Do not cross BBB hence cause minimal or no drowsiness Do not impair psychomotor performance Not relatively expensive.

35. 2 nd generation H1 blockers Uses Various allergic condtions like rhinits,dermatitis, conjuctivitis,urticaria,eczema,drug and food allergies. For allergic rhinitis– Fexofenadine, cetrizine,mezolastine,or rupatidine is used orally. Azelastine is used as nasal spray in allergic rhinitis. For urticaria ,atopic dermatitis,and other skin allergies fexofenadine,cetrizine, mezolastine,loratidine,and ebastineare useful. Azelastine and levocetrizine are available as eye drops for allergic conjuctivitis .

36. H2 BLOCKERS OR H2 ANTIHISTAMINICS OR H2 RECEPTOR ANTAGONISTS

37. MECHANSM OF ACTION Competitively block the H2 receptors in the parietal cells or oxyntic cells in the stomach. Inhibit gastric acid secretion by suppressing the 3 phases of acid secretion (i.e basal ,cephalic and gastric) They are mainly helpful in preventing nocturnal acid secretion. They prevent the acid secretion due to the stimulation of acetychokine , gastrin and food etc. Examples : Cimetidine (prototype drug) Rantiidne Famotidine (most potent) Nizatidine (nearly 100% bioavailibility)

38. Adverse effects 1. Antiandrogenic effect (shown by Cimetidine) 2. Gynaecomastia 3. Galactorrhea 4. Impotence 5. Nizatidine shows some adverse effects like bradycarrdia, lacrimation,salivation and diarrhoea

39. Uses Gastric and duodonal ulcer NSAID induced ulcer. GERD( Gastroesophageal reflux disorder) Zolinger- Elison syndrome Aspiration pneumonia

40. H3 RECEPTOR BLOCKERS

41. Mechanism of action Blocks the H3 receptors in brain and promotes the release of histamine in brain and thereby promotes wakefullness. Examples: Thioperamide Pitolisant Teprolisant Uses Narcolepsy ADHD (Attention deficit hyperactivity disorrder) Alzheimer’s Disease Schizphrenia

42. H4 RECEPTOR BLOCKERS

43. Mechanism of action Blocks the H4 RECEPTORS. Examples JNJ 7777120 VUF-6002  A987306 A943931 Pimozide Uses. 1.By inhibiting the H 4   receptor , asthma and allergy may be treated. 2.The highly selective histamine H 4   antagonist  VUF-6002 is orally active and inhibits the  activity  of both mast cells and eosinophils in vivo, and has antiinflammatory and antihyperalgesic  effects .

44. Some important drugs Betahistine a histamine analogue is used orally to treat vertigo in Mennier;s disease.Common side effects are nausea,vomitting, headaxhe,pruritus.it should be avoided in patients with asthma and peptic ulcer. Cetrizine is the active metabolite of hydroxyzine. Terfenadine is the fastest acting antihistaminic. Its active metabolite is fexofenadine. Asteimazole is the slowest and fongest acting antihistaminic. Asteimazole posseses the maximum topical activity

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