LSB384 Pharmacology for Health Professionals Local Chemical Mediators Autocoids/Local Hormones Sheila Doggrell PhD DSc sheila.doggrell@qut.edu.au

Histamine and Cytokines – Learning outcomes Classify, characterise and give examples of chemical mediators Outline the histamine system Explain the actions of histamine Discuss the mechanism of action, actions in the body, and clinical uses of named examples of medicines that modify the effects of histamine Describe the characteristics of cytokines Discuss the mechanism of action, actions in the body, and clinical uses of named examples of medicines that modify the effects of cytokines

Histamine and Cytokines – lecture plan Chemical mediators HISTAMINE The histamine system Actions of histamine Medicines that modify the effects of histamine CYTOKINES Cytokines Drugs that modify cytokines

Chemical mediators Classification Mediator Characteristics Example Nervous Neurotransmitter Release from neurones Short range Rapid action Acetylcholine Noradrenaline Endocrine Hormone Release from endocrine gland, Long range, Prolonged action Angiotensin Paracrine Local hormone Released from tissue Acts on neighbouring cells Relatively rapid Prostaglandins Nitric oxide Endothelin Autocrine Autocoid Confined to tissue Acts on self Histamine 5-HT Cytokines

Chemical mediators Classification Mediator Characteristics Example Nervous Neurotransmitter Release from neurones Short range Rapid action Acetylcholine Noradrenaline Endocrine Hormone Release from endocrine gland, Long range, Prolonged action Angiotensin Paracrine Local hormone Released from tissue Acts on neighbouring cells Relatively rapid Prostaglandins Nitric oxide Endothelin Autocrine Autocoid Confined to tissue Acts on self Histamine 5-HT Cytokines

Chemical mediators Responses to chemical mediators including local mediators are receptor mediated Drugs that modify the effects of local mediators are often agonists or antagonist of the receptor Probably, the next most common way of modifying the responses to local mediators is to inhibit the synthesis of the mediator

Autocoids/Local Hormones Histamine Cytokines

Histamine - introduction The highest concentrations of histamine in the body are stored in mast cells, a cell found in connective tissue that contains granules of chemicals including histamine In the periphery, histamine is an autocoid The two best characterised effects of histamine are its major roles in allergy and in gastric secretion In the central nervous system, histamine is a neurotransmitter and neuromodulator

Histamine system - 1 Storage Histamine is mainly stored in secretory granules in mast cells, and basophils (circulating equivalent of mast cells) Highest levels of histamine are found in lungs, followed by the mucous membranes, skin, stomach, and central nervous system

Histamine system - 2 Release With tissue damage or in hypersensitivity reactions, mast cells release their contents including histamine Receptors H1-receptor-mediated hypersensitivity (allergy) H2-receptor-mediated gastric acid secretion

Histamine actions - Type 1 Allergic reaction = anaphylactic reactions = immediate hypersensitivity reaction = commonly called allergy Grass pollen, house dust mites, certain foods, animal fur…. Medicines: Aspirin, Angiotensin converting enzyme inhibitors, penicillin

Histamine actions - Type 1 Allergic reaction Release of contents of mast cells and basophils – including histamine, eicosanoids and cytokines Causes vasodilation, oedema, and inflammation Different sites can be affected Food allergies affect gastrointestinal tract Skin; urticaria (hives) and atopic dermatitis (itching + raised red rash) Respiratory system: rhinitis and asthma Vasculature: anaphylactic shock (excessive vasodilation and bronchoconstriction)

Histamine actions - Type 1 Allergic reaction LUNG Hypersensitivity reaction Histamine H1-receptor-mediated bronchoconstriction

Histamine actions - Type 1 Allergic reaction NASAL MUCOUS MEMBRANES/SKIN – Hypersensitivity reaction H1-receptor-mediated dilation of terminal arterioles → build up of red blood cells → redness in allergy In anaphylaxis, excessive vasodilation causes hypotension H1-receptor-mediated contraction of the endothelial cells of capillaries → increases the space between the cells → allowing contents of capillaries (fluids, proteins) to flow into extracellular space to cause oedema (hives)

Histamine actions - Type 1 Allergic reaction Cartoon of histamine causing edema Endothelial cells Blood vessel H1 Lumen H1 Histamine Proteins, fluids Extracellular space Proteins, fluids Edema

Histamine actions – Acid secretion Ach Gastrin Histamine PARIETAL CELL H2 CCK3 M3 Ca2+ K+ H+/K+ ATP-ase H+ CCK = Cholecystokinin M = Muscarinic

Histamine – Drugs that modify - 1 Histamine system Theoretically, the effects of histamine can be modified at every level of the system – synthesis, release, receptors, cell signaling and breakdown With histamine we have important drugs that modify at the level of release and receptors Synthesis Release Action/Receptors Action/Cell Signal Breakdown

Histamine – Drugs that modify - 2 RELEASE Type 1 allergy The release of histamine and leukotrienes from mast cells is inhibited by cromoglycate Occasionally in the maintenance treatment of asthma Not useful after contents of mast cells, including histamine and leukotrienes has been released

Histamine – Drugs that modify - 3 RECEPTORS – antagonists at H1-receptors Antagonists at H1-receptors are commonly used in the treatment of Allergic rhinitis Conjunctivitis Chronic urticaria The 1st generation (older) H1-receptor antagonists also cross the blood brain barrier and cause sedation

Histamine – Drugs that modify - 4 RECEPTORS – antagonists at H1-receptors Examples of 1st generation H1-receptor antagonists include dexchlorpheniramine and diphenyhydramine Dexchlorpheniramine is still used in the treatment of allergic rhinitis, and chronic urticaria Diphenyhydramine is no longer used for hypersensitivity reactions, but is used as a mild sedative in insomnia

Histamine – Drugs that modify - 5 RECEPTORS – antagonists at H1-receptors 2nd generation H1-receptor antagonists are less able to cross the blood brain barrier and cause less sedation Examples include fexofenadine Used in the treatment of allergic rhinitis, and chronic urticaria

Histamine – Drugs that modify – 5 RECEPTORS – antagonists at H2-receptors Revolutionized the treatment of peptic acidity conditions such as peptic ulcer disease, gastro-oesphogus reflux disease (GORD), and dyspepsia, as there had been no good treatments previously An example of an H2-receptor antagonist is ranitidine (Ranitic) Ranitidine is a relatively safe drug and is available OTC in low doses

Histamine – Drugs that modify – 6 RECEPTORS – antagonists at H2-receptors As histamine acting at the H2-receptor is only one of the stimulants of acid secretion, H2-receptor antagonists are only effective against this component There are other stimulants of gastric secretion – H2-receptor antagonists do not inhibit this secretion whereas proton pump inhibitors do Proton pump inhibitors are often preferred to H2-receptor antagonists in peptic acidity conditions

Histamine H/2 receptor antagonism vs Proton pump inhibitor Gastrin Ach Histamine Histamine H/2 Receptor antagonist PARIETAL CELL H2 CCK3 M3 Ca2+ K+ H+/K+ ATP-ase H+ CCK = Cholecystokinin M = Muscarinic PROTON PUMP INHIBITORS

Autocoids/Local hormones Cytokines

Cytokines - general General Small secreted proteins that mediate and regulate inflammation, immunity, hematopoiesis Generally act over short distances, short time spans, and at very low concentrations Act to alter gene expression Interleukins are cytokines made by one leukocytes and acting on other leukocytes

Cytokines - inflammation Inflammation – interleukins There are many interleukins, but IL-1 is the main one associated with inflammation IL-1 stimulates T-lymphocytes to produce IL-2, which promotes inflammation, and causes fever IL-2 stimulates growth and activation of other T cells and NK (Natural Killer) cells (inflammation and immunity) ANAKINRA is an IL-1 antagonist used in the severe inflammation associated with rheumatoid arthritis

IL-1 Receptor antagonist: Anakinra T-Lymphocyte IL-1 R Antagonist IL-2 T-cells NK-cells Fever Inflammation and immunity

Cytokines – Drugs that modify Anakinra Subcutaneous administration Anakinra commonly causes allergy Treatment has the possibility of allowing serious infection

Cytokines - inflammation Inflammation – tumour necrosis factor Tumour necrosis factor (TNF) is the other cytokine that has a prominent role in inflammation TNF kills tumour cells – hence name TNF stimulates activities of T cells and eosinophils, which are involved in inflammation

Cytokines – Drugs that modify Tumour necrosis factor (TNF) is the other cytokine that has a prominent role in inflammation INFLIXIMAB is an antibody to TNF During treatment with infliximab, bacterial infection is infrequent Used intravenously, every 8 weeks Infliximab used in the treatment of rheumatoid arthritis and ankylosing spondylitis (degenerative inflammatory arthritis affecting the spine and sacroiliac joints)

LSB384 Pharmacology for Health Professionals Local chemical mediators Eicosanoids Dr Sheila Doggrell

Eicosanoids and their inhibitors – Learning Outcomes Outline the cyclooxygenase and lipooxygenase pathways Describe the actions of the eicosanoids Discuss, with named examples, the mechanism of action, actions in the body, and clinical uses of medicines that modify the eicosanoid system

Eicosanoids and their inhibitors – Lecture plan Introduction Systems Cyclooxygenase Lipooxygenase Actions Prostaglandins (PGs) Thromboxanes (TXs) Leukotrienes (LTs) Drugs that modify/Clinical uses

Introduction Eicosanoids = Arachidonic acid derivatives Prostaglandins (PGs), Thromboxanes (TXs), Leukotrienes (LTs) are local hormones – have effects close to where they are produced

Cyclooxgenase and Lipoxygenase system Dietary Linoleic Acid Phospholipids cell membrane Meat Arachidonic Acid Phospholipase A2 Cyclooxygenase pathway PROSTAGLANDINS and THROMBOXANES Stimuli Physical Chemical Hormonal Neuronal Immunological Lipooxygenase pathway LEUKOTRIENES

Alternative Cyclooxygenase Pathway Anandamide Cyclooxygenase (COX) -2 Prostamides Anandamide is the endogenous cannabinoid neurotransmitter Prostamides are prostaglandin-ethanolamides (structurally similar to prostaglandins) Receptors for prostamides are different from the receptors for prostaglandins

Cyclooxgenase and Lipoxygenase system EICOSANOIDS produced Prostaglandins (PGs), Thromboxane (A2) Leukotrienes (LTs) PGI2 is also known as Prostacyclin RECEPTORS Effects are local and receptor mediated – no prolonged effects due to recirculation PGD2 acts at DP receptors PGE2 acts at EP receptors (two types EP1 and EP2) PGF2α acts at FP receptors PGI2 acts at IP receptors TXA2 acts at TP receptors LTs acts at LT receptors

Cyclooxgenase and Lipoxygenase system Actions of the eicosanoids: Prostaglandins, Thromboxane, Leukotrienes

Actions – pain and inflammation Stimuli: Physical Chemical Bacterial Immunological PGs and LTs INFLAMMATION PAIN PGE2 and I2 Sensitise afferent nerve endings Amplification of pain OEDEMA LTs Increased vascular permeability Proteins leave blood vessels ERYTHEMA LTs and PGs Vasodilation = Redness Congestion of blood vessels

Actions – fever FEVER Increased PGE2 synthesis in hypothalamus PGs increase set point of body temperature Increased body temperature probably helps fight bacterial infections by killing the bacteria Tissue damage Malignancy Infections FEVER Disease

Actions – Cardiovascular – 1 PGs cause vasodilation of most vascular beds PGE2 and PGI2 keep ductus arteriosus open (lung bypass prior to birth) TXA2 causes vasoconstriction of most vascular beds PGI2 prevents platelet aggregation TXA2 increases platelet aggregation

Actions – Cardiovascular – 2 The prostacyclin produced by the endothelial cell lining of blood vessels prevents platelet aggregation Endothelium COX PGI2 Bone marrow Platelets AC =Adenylate cyclase ATP cAMP Inhibits Pl-Pl aggregation AC IP receptor Platelet

Actions – Cardiovascular – 3 Platelets stick to collagen and this activates the production of TXA2 and platelet aggregation Collagen AC =Adenylate cyclase TXA2 ATP  cAMP Promotes Pl-Pl aggregation TP receptor AC + COX-1 TXA2

Actions – Cardiovascular – 4 Under normal conditions platelet-platelet aggregation promotes blood vessel repair Excessive platelet-platelet aggregation can partially block the blood vessel Blood flow can dislodge the clump of platelets and they can move downstream to block a smaller vessel → thrombi (thrombosis) Drugs are used to inhibit platelet aggregation

Actions - Cytoprotection Protection from the damaging effects of acid in the gastrointestinal tract Stomach: COX-1 PGE2 and PGI2 Parietal cell Mucus secretion EP IP INHIBITS Gastric secretion Pepsin and HCl Stimulates Histamine Food Gastrin

Actions – Induction of labour Uterus PGs produced too early → Premature labour → Preterm birth PGE2 and PGF2α Oxytocin Contraction of the uterus Labour

Actions – immediate type hypersensitivity Lung LTC4,, LTD4, and LTE4 are potent bronchoconstrictors LTB4 chemotractant for neutrophils and eosinophils LTs stimulate mucus production Antigen-Antibody reaction Mast cell Release of Histamine H1- receptor-mediated Bronchoconstriction Synthesis and Release of Leukotrienes LT receptors Bronchoconstriction Bronchospasm Oedema

Drugs that modify the effects of eicosanoids Synthesis Phospholipase A2 Glucocorticoids LOX Non-selective COX inhibitors: aspirin, paracetamol, ibuprofen, piroxicam Selective COX-2 inhibitors: Celecoxib, diclofenac Synthesis COX Misoprostol Dinoprostone Iloprost Latanoprost EP receptor IP receptor FP receptor

Drugs that modify – Synthesis inhibitors INHIBIT PHOSPHOLIPASE A2 Glucocorticoids inhibit phospholipase A2 Not the only mechanism of glucocorticoids Glucocorticoids are potent anti-inflammatory agents Phospholipids of cell membrane Phospholipase A2 Inhibit with GLUCOCORTICOIDS Arachidonic acid COX LOX Decreased levels of PGs, TXs and LTs

Drugs that modify – Synthesis inhibitors INHIBIT COX Aspirin is a non-selective inhibitor of COX Group of non selective inhibitors of COX are known as the NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Aspirin, paracetamol, ibuprofen, piroxicam COX inhibitors do not reduce the levels of LTs Arachidonic acid COX Inhibit with aspirin PGs and TXs Decreased levels of PGs and TXs

Aspirin – clinical uses Irreversible non-selective inhibitor of COX MILD ANALGESIC ANTI-PYRETIC Partially ANTI-INFLAMMATORY Low dose inhibits platelet aggregation by preferentially blocking synthesis of TXA2 Used to prevent myocardial infarction/thrombosis

Aspirin and Platelet Aggregation Platelets do not have a nucleus (can’t synthesise COX-1), and only have a small supply of COX-1. Low dose aspirin irreversible inhibits COX-1 in platelets, decreasing the amount of intermediates available to be converted to TXA2 in the presence of thromboxane synthetase, decreasing platelet aggregation

Aspirin and Platelet Aggregation Endothelial cells have a plentiful supply of COX-1, and can synthesise more COX-1. Low dose aspirin has no significant effect on the COX-1 or on the production of PGI2 Low dose aspirin selectively inhibits TXA2 formation to reduce platelet aggregation Low dose aspirin is used to prevent myocardial infarction and stroke High dose aspirin inhibits both PGI2 and TXA2 formation and has NO EFFECT on platelet aggregation

Aspirin inhibits cytoprotection Inhibits protection from the damaging effects of acid in the gastrointestinal tract Stomach: Aspirin inhibits COX-1 PGE2 and PGI2 Parietal cell Mucus secretion EP IP Inhibition Gastric secretion Pepsin and HCl Stimulates Histamine Food Gastrin

Aspirin-INDUCED ULCERS Non-Steroidal Anti-Inflammatory Drugs that are non-selective inhibitors of cyclooxygenase (COX) (e.g. aspirin) Inhibit the cytoprotective effect of PGI2 PGE2 Ulcerogenic Chronic users of aspirin for its antithrombotic effect or of the other NSAIDs for analgesia, have a 2-4% of developing an ulcer.

Aspirin-induced hypersensitivity: asthma and angiodema Inhibition of cyclooxygenase  Build up of arachidonic acid  metabolised to leukotrienes  rhinitis, asthma and angiodema 5-10% of asthmatics are sensitive to aspirin Avoid all NSAIDs after a hypersensitivity reaction ARACHIDONIC ACID CYCLOOXYGENASE 5-LIPOOXYGENASE NSAID s PROSTAGLANDINS LEUKOTRIENES

Paracetamol (Panadol) Mechanism of Action: Cyclooxygenase (COX) inhibitor Actions: Decreases levels of Prostaglandins Therapeutic effect: Reduces Pain and Fever PATHOLOGICAL e.g. bacterial insult ARACHIDONIC ACID Cell membrane PARACETAMOL CYCLOOXYGENASE  PROSTAGLANDINS BACTERIAL INFECTION  PAIN  FEVER

PARACETAMOL – Actions Analgesic, antipyretic NOT anti-inflammatory - ? – possibly products of inflammation stop paracetamol from inhibiting COX Have to use aspirin or other NSAIDs in the treatment of inflammation

PARACETAMOL – Actions No effect on platelet aggregation or clotting (The effect of low dose aspirin to inhibit platelet aggregation and clotting may depend on it being an irreversible inhibitor) Cannot substitute paracetamol for aspirin for cardioprotection, as it is not anti-thrombotic

Ibuprofen Ibuprofen (Nurofen) Non-selective COX inhibitor Used as analgesic, anti-pyretic and anti-inflammatory Effective in pain of low-to-moderate intensity – nonspecific relief of minor aches and pain (headache, arthritis, dysmenorrhea, neuralgia, myalgia) Also used in chronic conditions such as rheumatoid arthritis, osteoarthritis

Ibuprofen Ibuprofen vs Aspirin Ibuprofen has similar efficacy (maximum response) to aspirin Greater tolerability (less ulcers) than aspirin on chronic use Lesser ability to inhibit platelet aggregation than aspirin → not suitable for secondary prevention of myocardial infarction or stroke

Piroxicam PIROXICAM Non-selective COX inhibitor Independently of COX inhibition, inhibits the activation of neutrophils – contributes to anti-inflammatory action Good anti-inflammatory agent Used in treatment of rheumatoid arthritis and osteoarthritis

Piroxicam PIROXICAM Active after oral administration Slow onset of action, and slow to reach steady state (7-12 days) T1/2 of elimination is about 50 hours Because of slow onset of action is not used in acute conditions (pain, fever) Used in the long term treatment of chronic conditions such as rheumatoid arthritis and osteoarthritis

Rationale for selective COX-2 inhibitors COX has two forms, COX-1 is constitutively expressed (always active e.g. stomach) whereas COX-2 is induced in response to stimuli Selective COX-2 inhibitors should give less bleeding NSAIDS INHIBITS COX-2 Reduces pain and inflammation INHIBITS COX-1 Reduces levels of Cytoprotective PGs

Selective COX-2 inhibitors - rofecoxib Rofecoxib is the most selective COX-2 inhibitor marketed to date Trials showed that rofecoxib was very effective against the pain and inflammation of chronic conditions such as osteoarthritis and rheumatoid arthritis There was less gastrointestinal toxicity with rofecoxib than with non-selective NSAIDs Rofecoxib was withdrawn for causing a slight increase in cardiovascular toxicity

Selective COX-2 inhibitors - celecoxib Celecoxib (Celebrex) is not as COX-2 selective as rofecoxib Failed to establish less gastrointestinal toxicity than non-selective NSAIDs Cardiotoxicity is borderline and/or disputed with celecoxib Has a warning not to be used in subjects with cardiovascular or cerebrovascular disease

Selective COX-2 inhibitors - celecoxib Active after oral administration, lipophilic and widely distributed, t1/2 of elimination = 11 hours Relief from inflammation in osteoarthritis and rheumatoid arthritis Relief from post-extraction dental pain

Selective COX-2 inhibitors - Diclofenac Although it has been around for many years, only recently has diclofenac (Voltaren) been shown to be a selective inhibitor of COX-2 Selectivity for COX-2 similar to celecoxib Gastrointestinal toxicity and cardiotoxicity of diclofenac is similar to that of celecoxib

Selective COX-2 inhibitors - Diclofenac Rapid absorption, short t1/2 (1-2 hours) Analgesic, antipyretic, and anti-inflammatory Long term use in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis (form of arthritis that affects the spine) Short term use in acute musculoskeletal pain, postoperative pain, and dysmenorrhea

Gastrointestinal protection from COX inhibitors - misoprostol NSAIDs can cause ulcers To prevent this, diclofenac is available in combination with misoprostol Misoprostol is agonist at EP receptors Inhibits gastric acid secretion Provides gastric cytoprotection Decreased gastrointestinal toxicity with diclofenac

Gastrointestinal protection from COX inhibitors - PPIs NSAIDs can cause ulcers Proton pump inhibitors (PPIs) inhibit the production of acid PPIs can be used to give gastrointestinal protection

Gastrointestinal protection from COX inhibitors - PPIs OMEPRAZOLE is the prototype PPI There are other –prazoles (ESOMEPRAZOLE) Used in the treatment of peptic ulcer, gastric reflux etc Prevention and/or treatment of gastrointestinal adverse effects of NSAIDs

Drugs that modify – Receptors AGONISTS AT PROSTAGLANDIN RECEPTORS: EP MISOPROSTOL Selective EP1 receptor agonist Developed for gastric cytoprotection Suppresses gastric ulceration As effective as H2-receptor antagonists in peptic ulcer Not commonly used as proton pump inhibitors are preferred Used as cytoprotective with diclofenac When used for gastric cytoprotection is contraindicated in pregnant women as is a powerful uterine stimulant Off-label development as uterine stimulant

Drugs that modify – Receptors AGONISTS AT PROSTAGLANDIN RECEPTORS: EP MISOPROSTOL When pregnancy is complicated by early death, misoprostol is used to remove the remnants Misoprostol is used with the progesterone antagonist mifepristone for early abortion Adverse effect when using misoprostol as a uterine stimulant are gastrointestinal (diarrhoea)

Drugs that modify – Receptors AGONISTS AT PROSTAGLANDIN RECEPTORS: EP Dinoprostone Selective EP2 receptor agonist Increases contractions of uterus Relaxes cervix Induction or augmentation of labour especially when cervix is not dilating

Drugs that modify – Receptors AGONISTS AT PROSTAGLANDIN RECEPTORS: IP Prostacyclin inhibits platelet aggregation and is a potent vasodilator PGI2 is not active after oral administration, and is rapidly broken down – continuous infusion is required

Drugs that modify – Receptors AGONISTS AT PROSTAGLANDIN RECEPTORS: IP ILOPROST is a synthetic analog of PGI2 Iloprost has a longer half-life than PGI2 Iloprost is used in the treatment of pulmonary hypertension Iloprost is delivered by nebulizer Local high pulmonary concentration → localised pulmonary vessel dilation

Drugs that modify – Receptors AGONISTS AT PROSTAGLANDIN RECEPTORS: FP Ciliary muscle of the eye has FP receptors Stimulation of these receptors increases the aqueous humour outflow from the eye LATANOPROST is an ester analog of PGF2α, and selective agonist of FP receptors Used in the treatment of ocular hypertension

Drugs that modify - Receptors Agonist at Prostamide receptors Bimatoprost Pronounced lowering of intraocular pressure Potent and highly effective in ocular hypertension Increases aqueous outflow Used topically in glaucoma

LSB384 Pharmacology for Health Professionals Local mediators 5-Hydroxytryptamine Nitric oxide Endothelin

5-Hydroxytryptamine (5-HT) 5-HT is a neurotransmitter and a local chemical mediator 5-HT1 receptor subtypes and 5-HT2 receptors are involved in migraine 5-HT3 and 5-HT4 receptors are involved in gastrointestinal motility Excessive cranial blood vessel dilation and inflammation underlies the pain of migraine

Ergotamine and migraine From poison to therapy Ergot alkaloids are the product of a fungus that grows on corn Eat the contaminated corn and it causes plague – intense vasoconstriction of the extremities leading to gangrene, and stimulation of the uterus causing abortion

Ergotamine and migraine Ergotamine is one of the ergot alkaloids The actions of ergotamine include being a partial agonist at 5-HT1B/1D receptors Stimulation of the 5-HT1B/1D receptors on cranial blood vessels causes vasoconstriction Vasoconstriction with ergotamine overcomes the excessive vasodilation of migraine

Ergotamine and migraine Vasoconstriction 5-HT1B/1D 5-HT1B/1D Normal blood vessel diameter Excessive Vasodilation

TRIPTANS and migraine SUMATRIPTAN is a 5-HT1B/1D agonist used in the treatment of migraine attacks The central nervous system is involved in the excessive vasodilation of migraine Stimulation of 5-HT1B/1D receptors in the central nervous system may decrease the release of neurotransmitter onto the cranial blood vessels, and the excessive vasodilation Secondly, as with ergotamine, triptan stimulation of the 5-HT1B/1D receptors on the cranial blood vessels will cause vasoconstriction to overcome the excessive vasodilation

TRIPTANS and migraine Brain 5-HT1B/1D Sumatriptan Inhibits neurotransmitter release Vasoconstriction 5-HT1 5-HT1 Neurotransmitter release Normal blood vessel diameter Excessive Vasodilation

SUMITRIPTAN In an attack of migraine, need a drug that acts quickly to relieve Oral bioavailability of sumitriptan is low (15%) After oral administration of sumitriptan, peak plasma concentrations are not reached for 1-2 hours, and onset of action may take up to 30 min After subcutaneous or nasal spray administration of sumitriptan, the bioavailability is increased and the onset of action may occur in 15 min

Drugs to prevent migraine attacks Include the serotonin receptor antagonist (predominantly 5-HT2 receptor antagonist) – PIZOTIFEN The action of pizotifen in preventing migraine is unknown Two-thirds of patients have a 50% reduction in frequency of headache with pizotifen Pizotifen cause drowsiness

5-HT and gastrointestinal tract 5-HT3-RECEPTOR ANTAGONISTS 5-HT stimulates 5-HT3-receptors to increase vomiting -etrons: ONDANSETRON (prototype) are selective 5-HT3-receptor antagonist Inhibition of emesis Most effective agents for treating chemotherapy-induced nausea and vomiting

Nitric oxide Nitric oxide (NO) is a neurotransmitter and a local chemical mediator As local chemical mediator relaxes blood vessels NITROVASODILATORS: Nitroglycerin, Isosorbide-5-mononitrate Nitrovasodilators release NO, which relaxes blood vessels

Nitric oxide Nitroglycerin, Isosorbide-5-mononitrate Used in treatment and prevention of angina (diseased coronary arteries) Diseased coronary arteries are difficult to dilate Nitrovasodilators have little effect on diseased coronary arteries Nitrovasodilators end an angina attack by causing venodilation, and reducing the workload on the heart

NITROVASODILATORS Nitroglycerin Extensive 1st pass liver metabolism Sublingual tablet or spray (faster) in attack Onset of action within a minute t1/2 about 3 minutes Patches or ointment for prevention of anginal attacks

Isosorbide-5-mononitrate No significant 1st pass liver metabolism Oral NITROVASODILATORS Isosorbide-5-mononitrate No significant 1st pass liver metabolism Oral Prevention of angina attack

Nitric oxide and erectile dysfunction Sildenafil for Erectile Dysfunction Corpus carvenosum Endogenous Nitric oxide Guanylate Cyclase Sildenafil Phosphodiesterase V ↑cGMP ↑ Relaxation ↑ Penile erection Inactivation GTP

ENDOTHELIN Endothelin is a peptide local hormone It is a potent vasoconstrictor High levels/sensitivity in pulmonary circulation in certain forms of pulmonary hypertension

ENDOTHELIN BOSENTAN = Non-selective endothelin receptor antagonist Active after oral administration Reduces pulmonary pressure Reduces the incidence of death, lung transplantation, and hospitalization for pulmonary hypertension