Amine Autacoids Histamine & 5-Hydroxytryptamine Dr Mahmoud Khattab 22/12/08 M Khattab

Histamine Source, Storage & Release Histamine is an amine, derived from the amino acid histidine by L-histidine decarboxylase Storage: In mast cells mainly in lungs, skin & GIT mucosa, as an inactive complex with heparin In platelets & basophilic leukocytes In CNS Enterochromaffin-like (ECL) cells of the stomach Histamine inactivation is via N-methylation or oxidative deamination into Me-histamine/imidazole acetic acid 22/12/08 M Khattab

Histamine Release Immunologic Release (Cell destruction): mast cell & basophils degranulate when exposed to the appropriate antigen (bacterial toxins, sing venom, cold, injury) Chemical Release: by drugs like morphine, vancomycin & curare, X-ray contrast media, foreign proteins Dissolution of cytoplasmic granules by radiation and surfactants 22/12/08 M Khattab

Histamine Receptors & Mechanism of Action Histamine has four histamine H1, H2, H3, & H4 G-protein coupled receptors Vasodilatation is via endothelial H1 receptors & smooth muscle H2 receptors H1 stimulation → Increased intracellular Ca2+ → Activation of PLA2 → PGI2 & NO production → Diffusion to smooth muscles → vasodilatation Contraction of bronchi, intestine & large blood vessels occur via stimulation of PLC-coupled H1 receptors followed by increased IP3 & DAG 22/12/08 M Khattab

Histamine Receptors & Mechanism of Action Gastric acid secretion is via parietal cells H2 receptor stimulation by histamine from ECF cells H2 receptor stimulation→ increased c.AMP → activation of H+/K+-ATPase (proton pump) H3 receptors are located both in the CNS (histamine is a neurotransmitter) & in the periphery Histamine on H3 receptors inhibits its own release (autoreceptors) as well as inhibition of release of other neurotransmitters (hetero-inhibitory effect) H3 receptors appear to be coupled to Ca2 influx reduction through N-type Ca2+ channels 22/12/08 M Khattab

Actions of Histamine Increased vascular permeability (H1 & H2): capillary dilation & increased permeability of post-capillary venules → leakage of plasma proteins & fluids into extracellular spaces This leads to the dermal “triple response” upon local injury: redness, wheal formation, & flare Heart: Increased heart rate (H2) and positive inotropic effect (H1 & H2), at moderate-high dose Sensory nerve endings stimulation leading to pain & itching 22/12/08 M Khattab

Actions of Histamine Stimulation of exocrine glands secretions: Nasal & bronchial secretions (H1 receptors) Gastric acid secretion (H2 receptors) Stimulation of epinephrine secretion from adrenal medulla via stimulation of H1 receptors on chromaffin cells Possible pathophysiologic role in migraine 22/12/08 M Khattab

Histamine H1 Receptor Blockers (Antihistamines) Ethanolamines: Diphenhydramine, Dimenhydrinate* Ethylenediamines: Tripelennamine, antazoline, naphazoline Alkylamines: Chlorpheniramine, brompheniramine Piperazines: Cyclizine*, meclizine*, cetrizine (2ndgeneration) Phenothiazines: Promethazine Piperidines: (New, Second-Generation) Loratidine, desloratidine, fexofenadine * Mainly used for prevention of nausea, vomiting & motion sickness 22/12/08 M Khattab

Antihistamines Mechanism of Action: Competitive inhibitors for histamine at H1 receptors (structural analogs) They antagonize all actions of histamine except for the gastric acid stimulation & H2-mediated vasodilatation Pharmacokinetics: Well absorbed orally, max serum level in 1-2 hrs Old first-generation agents have wide tissue distribution including CNS Newer 2nd generation are not (non-sedative) Duration of older members: 4-6 hrs, piperazine derivatives & 2nd generation drugs have a long duration of ≥24 hrs 22/12/08 M Khattab

Antihistamines Pharmacological Actions Inhibition of histamine-induced contraction of respiratory & GIT smooth muscles Abolish H1-mediated vasodilatation & increased capillary permeability Reduction of salivary, histamine-mediated bronchial & lacrimal secretions Most antihistamines cause CNS depression, but in some patients restlessness may occur. The antimotion sickness effect is partly mediated through the anti-cholinergic effect 22/12/08 M Khattab

Antihistamines Receptors Blocked & Adverse Actions Receptors selectivity: 1st generation antihistamines are of poor H1 receptor selectivity. They block other receptors leading to adverse effects: Cholinergic R blockade: dry mouth, urinary retention, & tachycardia -adrenergic R blockade, by promethazine, leading to hypotension, tachycardia & dizziness Serotonin R blockade leading to increased appetite 22/12/08 M Khattab

Antihistamines Adverse Actions Sedation: 1st generation antihistamines have high CNS penetration leading to sedation In addition, they may cause tremors, dizziness, tinnitus & fatigue 2nd generation antihistamines have no or minor sedation and other CNS effects being more specific for H1 & poor CNS penetration This might interfere with driving ability or to work machinery (use second generation) Anticholinergic side effects especially dry mouth & blurred vision 22/12/08 M Khattab

Antihistamines Adverse Actions Local anesthetic activity that can lead, at high dose level to: CNS stimulation & convulsions, (observed in attempted suicide with antihistamines) Cardiac depression Drug interactions; increasing CNS sedation of other sedatives, increased activity when given with CYT P450 inhibitors (terfenadine was withdrawn) Acute poisoning: hallucination, excitement, & convulsions (fever & flushed skin in children) If untreated, it leads to coma & cardiorespiratory depression 22/12/08 M Khattab

Antihistamines Therapeutic Uses Allergic Conditions Acute allergic rhinitis (hay fever) Acute skin reactions (urticaria, drug rashes) NOT in bronchial asthma or chronic skin allergies Prevention of motion sickness & CTZ/vestibular nausea: cyclizine, meclizine & dimenhydrinate are the most effective members OTC Sedative/hypnotics for insomnia treatment: Diphenhydramine & doxylamine have strong sedative effect 22/12/08 M Khattab

Histamine H2 Receptor Blockers No or little H1 receptor affinity They block H2 receptors on gastric parietal cells attenuating gastric acid secretion Main use is treatment of peptic ulcer Agents include Cimetidine Ranitidine Famotidine 22/12/08 M Khattab

5-Hydroxytryptamine (5-HT, Serotonin) Serotonin is an amine synthesized from L-tryptophan by an hydroxylase enzyme MAO & aldehyde de-hydrogenase degrade 5-HT into 5-hydroxyindoleacetic acid (5-HIAA) Storage: 90% is present in enterochromaffin cells of the GIT Other in platelets & CNS 22/12/08 M Khattab

Serotonin Receptors & Functions Seven receptors, 5-HT1- 5-HT7 for serotonin are characterized, the first four have related functions All types are G-protein coupled receptor except 5-HT3 receptors that are inotropic receptors 22/12/08 M Khattab

Serotonin Pharmacological Actions CNS: 5-HT plays a role in regulation of mood, food intake & sleep (5-HT1A-D) Blood vessels: Vasodilation (5-HT1A-D) in skeletal muscles & coronaries & cerebral constriction Vasoconstriction (5-HT2, PLC-coupled) in splanchnic, renal, pulmonary vasculature Heart: increased heart rate & contractility (5-HT1) Reflex cardiac slowing & hypotension via 5-HT3 receptor stimulation in coronaries & baroceptors Stimulation of platelet aggregation 22/12/08 M Khattab

5-HT Receptor Agonists (5-HT RAs) (Triptans) 5-HT analogues that are agonists on 5-HT1A/1D showed effectiveness against migraine In migraine, evidence indicates the activation of the trigemino-vascular system leading to dilation & neurogenic inflammation (antidromic release of proiflammatory peptides & neuropeptides) Mechanism: 5-HTRAs stimulate 5-HT1A/1D receptors in the intracranial vasculature & sensory nerves of the trigeminal system leading to: Cerebral vasculature vasoconstriction Inhibition of release of proiflammatory peptides (kinins) & neuropeptides 22/12/08 M Khattab

5-HT Receptor Agonists (5-HT RAs) (Triptans) Eletriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan Use: Acute treatment of attacks +/-aura, not for prophylaxis Not used in hemiplegic or opthalmogenic migraine Not combined with ergotamine derivatives nor selective serotonin reuptake inhibitors (SSRIs) Contraindicated with coronary artery disease, congenital heart disease, atherosclerosis, severe hypertension or seizures Not used in patients below 18 (or <12 for Zolmitriptan) Safety in pregnancy/lactation not tested 22/12/08 M Khattab

5-HT RAs Adverse Effects & Pharmacokinetics Angina pectoris-like syndrome, arrhythmias, CA spasm, MI, cerebral hemorrhage, stroke & increased blood pressure in susceptible patients Pharmacokinetics: Mostly significant pain relief within 4 hours Severe renal/hepatic impairment can affect their biotransformation & clearance (dose reduction) Average oral bioavailability, sumatriptan being the lowest (14%) Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressants (Details in Depression): Fluoxetine, paroxetine, sertaline, citalopram 22/12/08 M Khattab

Other 5-HT Antagonists Ergot Alkaloids They are of fungal origin & used as oxytocic drugs, e.g., ergometrine (ergonovine) & Me-ergometrine Ergotamine & dihydroergotamine have 5-HT1D agonist activity, in addition to -adrenergic stimulation & direct vasoconstriction They are used in early-onset phase of migraine Used in combination with caffeine Adverse effects include nausea & vasoconstriction that may lead to angina or stroke Methysergide: discussed later slide 22/12/08 M Khattab

Peripheral 5-HT Antagonists Methysergide: Both antagonist on 5-HT receptors & a partial agonist Prophylactic migraine treatment It takes 1-2 days for full effect, Not used during acute attack Chronic use should not exceed 6 months without 3-4 weeks methysergide-free period Its frequent side effects limit its use; retro-peritoneal & pulmonary fibrosis, aortic/valular fibrosis, insomnia, alopecia Dose should be gradually tapered off for2-3 weeks to avoid rebound headache 22/12/08 M Khattab

Peripheral 5-HT Antagonists Pizotifen, a potent 5-HT & histamine antagonist used for migraine anaphylaxis reducing the frequency & severity of attacks Side effects include drowsiness, headache, potentiation of CNS depressants, dry mouth, impotence and hepato-toxicity (chronic use) Cyproheptadine, a potent 5-HT & histamine antagonist used as antipruritic agent In children, it may cause weight gain & increased growth rate 22/12/08 M Khattab

Peripheral 5-HT Antagonists Ketanserin , a 5-HT2 receptor antagonist It causes vasodilation lowering blood pressure, and considered for hypertension treatment It has - & H1- receptor blocking activity Ondansetron & granisetron are 5-HT3 receptor antagonists used for prevention of nausea & vomiting caused by radiotherapy or chemotherapy Side effects: headache, cardiac rhythm changes, 22/12/08 M Khattab