Amine Autacoids Histamine 5 Hydroxytryptamine Dr Mahmoud Khattab

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

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

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

Histamine Receptors & Mechanism of Action n Histamine has four histamine H 1, H 2, H 3, & H 4 G- protein coupled receptors n Vasodilatation is via endothelial H 1 receptors & smooth muscle H 2 receptors • H 1 stimulation → Increased intracellular Ca 2+ → Activation of PLA 2 → PGI 2 & NO production → Diffusion to smooth muscles → vasodilatation q Contraction of bronchi, intestine & large blood vessels occur via stimulation of PLC-coupled H 1 receptors followed by increased IP 3 & DAG 22/12/08 M Khattab

Histamine Receptors & Mechanism of Action n Gastric acid secretion is via parietal cells H 2 receptor stimulation by histamine from ECF cells Ø H 2 receptor stimulation→ increased c. AMP → activation of H+/K+-ATPase (proton pump) q H 3 receptors are located both in the CNS (histamine is a neurotransmitter) & in the periphery Ø Histamine on H 3 receptors inhibits own release (autoreceptors) as well as inhibition of release of other neurotransmitters (hetero-inhibitory effect) Ø H 3 receptors appear to be coupled to Ca 2 influx reduction through N-type Ca 2+ channels 22/12/08 M Khattab

Actions of Histamine n Increased vascular permeability (H 1 & H 2): capillary dilation & increased permeability of post-capillary venules → leakage of plasma proteins & fluids into extracellular spaces Ø This leads to the dermal “triple response” upon local injury: redness, wheal formation, & flare n Heart: Increased heart rate (H 2) and positive inotropic effect (H 1 & H 2), at moderate-high dose n Sensory nerve endings stimulation leading to pain & itching 22/12/08 M Khattab

Actions of Histamine q Stimulation of exocrine glands secretions: Ø Nasal & bronchial secretions (H 1 receptors) Ø Gastric acid secretion (H 2 receptors) q Stimulation of epinephrine secretion from adrenal medulla via stimulation of H 1 receptors on chromaffin cells q Possible pathophysiologic role in migraine 22/12/08 M Khattab

Histamine H 1 Receptor Blockers (Antihistamines) n Ethanolamines: Ø Diphenhydramine, Dimenhydrinate* n Ethylenediamines: Ø Tripelennamine, antazoline, naphazoline n Alkylamines: Ø Chlorpheniramine, brompheniramine q Piperazines: Cyclizine*, meclizine*, cetrizine (2 ) ndgeneration q Phenothiazines: Promethazine q Piperidines: (New, Second-Generation) ü Loratidine, desloratidine, fexofenadine * Mainly used for prevention of nausea, vomiting & motion sickness 22/12/08 M Khattab

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

Antihistamines Pharmacological Actions n Inhibition of histamine-induced contraction of respiratory & GIT smooth muscles n Abolish H 1 -mediated vasodilatation & increased capillary permeability n Reduction of salivary, histamine-mediated bronchial & lacrimal secretions n Most antihistamines cause CNS depression, but in some patients restlessness may occur. n The antimotion sickness effect is partly mediated through the anti-cholinergic effect 22/12/08 M Khattab

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

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

Antihistamines Adverse Actions n Local anesthetic activity that can lead, at high dose level to: Ø CNS stimulation & convulsions, (observed in attempted suicide with antihistamines) Ø Cardiac depression n Drug interactions; increasing CNS sedation of other sedatives, increased activity when given with CYT P 450 inhibitors (terfenadine was withdrawn) n Acute poisoning: hallucination, excitement, & convulsions (fever & flushed skin in children) Ø If untreated, it leads to coma & cardiorespiratory depression 22/12/08 M Khattab

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

Histamine H 2 Receptor Blockers n No or little H 1 receptor affinity n They block H 2 receptors on gastric parietal cells attenuating gastric acid secretion n Main use is treatment of peptic ulcer n Agents include Ø Cimetidine Ø Ranitidine Ø Famotidine 22/12/08 M Khattab

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

Serotonin Receptors & Functions n Seven receptors, 5 -HT 1 - 5 -HT 7 for serotonin are characterized, the first four have related functions n All types are G-protein coupled receptor except 5 HT 3 receptors that are inotropic receptors 22/12/08 M Khattab

Serotonin Pharmacological Actions n CNS: 5 -HT plays a role in regulation of mood, food intake & sleep (5 -HT 1 A-D) n Blood vessels: Vasodilation (5 -HT 1 A-D) in skeletal muscles & coronaries & cerebral constriction Ø Vasoconstriction (5 -HT 2, PLC-coupled) in splanchnic, renal, pulmonary vasculature q Heart: increased heart rate & contractility (5 -HT 1) ü Reflex cardiac slowing & hypotension via 5 -HT 3 receptor stimulation in coronaries & baroceptors q Stimulation of platelet aggregation 22/12/08 M Khattab

5 -HT Receptor Agonists (5 -HT RAs) (Triptans) n 5 -HT analogues that are agonists on 5 -HT 1 A/1 D showed effectiveness against migraine n In migraine, evidence indicates the activation of the trigemino-vascular system leading to dilation & neurogenic inflammation (antidromic release of proiflammatory peptides & neuropeptides) n Mechanism: 5 -HTRAs stimulate 5 -HT 1 A/1 D receptors in the intracranial vasculature & sensory nerves of the trigeminal system leading to: Ø Cerebral vasculature vasoconstriction Ø 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 q Use: Acute treatment of attacks +/-aura, not for prophylaxis Ø Not used in hemiplegic or opthalmogenic migraine Ø Not combined with ergotamine derivatives nor selective serotonin reuptake inhibitors (SSRIs) q Contraindicated with coronary artery disease, congenital heart disease, atherosclerosis, severe hypertension or seizures q Not used in patients below 18 (or <12 for Zolmitriptan) 22/12/08 M Khattab q Safety in pregnancy/lactation not tested

5 -HT RAs Adverse Effects & Pharmacokinetics n Angina pectoris-like syndrome, arrhythmias, CA spasm, MI, cerebral hemorrhage, stroke & increased blood pressure in susceptible patients n Pharmacokinetics: Ø Mostly significant pain relief within 4 hours Ø Severe renal/hepatic impairment can affect their biotransformation & clearance (dose reduction) Ø Average oral bioavailability, sumatriptan being the lowest (14%) q Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressants (Details in Depression): Ø 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 q Ergotamine & dihydroergotamine have 5 -HT 1 D agonist activity, in addition to -adrenergic stimulation & direct vasoconstriction q They are used in early-onset phase of migraine q Used in combination with caffeine q Adverse effects include nausea & vasoconstriction that may lead to angina or stroke q Methysergide: discussed later slide 22/12/08 M Khattab

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

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

Peripheral 5 -HT Antagonists n Ketanserin , a 5 -HT 2 receptor antagonist Ø It causes vasodilation lowering blood pressure, and considered for hypertension treatment Ø It has - & H 1 - receptor blocking activity n Ondansetron & granisetron are 5 -HT 3 receptor antagonists used for prevention of nausea & vomiting caused by radiotherapy or chemotherapy n Side effects: headache, cardiac rhythm changes, 22/12/08 M Khattab