Amine Autacoids Histamine & 5Hydroxytryptamine

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
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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
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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
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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 postcapillary 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 (2 Phenothiazines: Promethazine Piperidines: (New, Second-Generation) Loratidine, desloratidine, fexofenadine
* Mainly used for prevention of nausea, vomiting & motion sickness
22/12/08 M Khattab
ndgeneration

Antihistamines
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
Mechanism of Action:
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
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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
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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
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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
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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
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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 5HT3 receptors that are inotropic receptors
Type
5-HT1 5-HT2

Distribution
Brain, instetinal nerves Brain, heart, lungs, smooth muscle control, GI system, blood vessels, platelets Limbic system, ANS CNS, smooth muscle

Postulated Roles
Neuronal inhibition, behavioural effects, cerebral vasoconstriction Neuronal excitation, vasoconstriction, behavioural effects, depression, anxiety Nausea, anxiety Neuronal excitation, GI Not known

5-HT3 5-HT4

5-HT5, Brain 6, 722/12/08 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
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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
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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

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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
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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; retroperitoneal & pulmonary fibrosis, aortic/valular fibrosis, insomnia, alopecia Dose should be gradually tapered off for2-3 weeks to avoid rebound headache
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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