16 amine autacoids
TRANSCRIPT
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Amine AutacoidsHistamine & 5-
Hydroxytryptamine
Dr Mahmoud Khattab
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HistamineSource, Storage & Release
Histamine is an amine, derived from the aminoacid 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 oroxidative deamination into Me-histamine/imidazoleacetic 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 H1stimulation Increased intracellular Ca
2+
Activation of PLA2 PGI2& NO production
Diffusion to smooth muscles vasodilatation
Contraction of bronchi, intestine & large blood
vessels occur via stimulation ofPLC-coupled H1receptors 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
H2receptor 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
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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
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Actions of Histamine
Stimulation ofexocrine glands secretions:
Nasal & bronchial secretions (H1 receptors)
Gastric acid secretion (H2 receptors)
Stimulation ofepinephrine secretion from adrenal
medulla via stimulation of H1 receptors on
chromaffin cells
Possible pathophysiologic role in migraine
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Histamine H1 Receptor
Blockers (Antihistamines)
Ethanolamines:
Diphenhydramine, Dimenhydrinate*
Ethylenediamines:
Tripelennamine, antazoline, naphazoline Alkylamines:
Chlorpheniramine, brompheniramine
Piperazines: Cyclizine*, meclizine*, cetr izine(2ndgeneration)
Phenothiazines: Promethazine
Piperidines: (New, Second-Generation)
Lo rat idine, deslorat idine, fexofenadine
* Mainly used for prevention of nausea, vomiting & motion sickness
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Antihistamines
Mechanism of Action:Competitive inhibitors forhistamine at H1 receptors (structural analogs)
They antagonize all actions of histamine except forthe 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, piperazinederivatives & 2nd generation drugs have a long
duration of 24 hrs
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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 insome patients restlessness may occur.
The antimotion sickness effect is partly mediated
through the anti-cholinergic effect
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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, urinaryretention, & 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 highCNS penetration leading to sedation
In addition, they may cause tremors, dizziness,tinnitus & fatigue
2nd generation antihistamines have no or minorsedation and other CNS effects being morespecific for H1 & poor CNS penetration
This might interfere with driving ability or to workmachinery (use second generation)
Ant icho l inergic side ef fectsespecially dry mouth& blurred vision
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Antihistamines
Adverse Actions
Local anesthet ic act iv i tythat can lead, at highdose level to:
CNS stimulation & convulsions, (observed in
attempted suicide with antihistamines) Cardiac depression
Drug interactions; increasing CNS sedation ofother 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
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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
Type Distribution Postulated Roles
5-HT1 Brain, instetinal nerves Neuronal inhibition, behaviouraleffects, cerebral vasoconstriction
5-HT2 Brain, heart, lungs, smooth musclecontrol, GI system, blood vessels,platelets
Neuronal excitation, vasoconstriction,behavioural effects, depression,anxiety
5-HT3 Limbic system, ANS Nausea, anxiety
5-HT4 CNS, smooth muscle Neuronal excitation, GI
5-HT5,6, 7
Brain Not known
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Serotonin PharmacologicalActions
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/1Dshowed effectiveness against migraine
In migraine, evidence indicates the activation of
the trigemino-vascular system leading to dilation &neurogenic inflammation (antidromic release ofproiflammatory peptides & neuropeptides)
Mechanism: 5-HTRAs stimulate 5-HT1A/1D
receptors in the intracranial vasculature & sensorynerves 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
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5-HT RAs Adverse Effects &
Pharmacokinetics
Angina pectoris-like syndrome, arrhythmias, CAspasm, MI, cerebral hemorrhage, stroke &increased blood pressure in susceptible patients
Pharmacokinetics:Mostly significant pain relief within 4 hours
Severe renal/hepatic impairment can affect theirbiotransformation & clearance (dose reduction)
Average oral bioavailability, sumatriptan being thelowest (14%)
Selective serotonin reuptake inhibitors (SSRIs) areused as antidepressants (Details in Depression):
Fluoxetine, paroxetine, sertaline, citalopram
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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 -adrenergicstimulation & 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 without3-4 weeks methysergide-free period
Its frequent side effects limit its use; retro-peritoneal & pulmonary fibrosis, aortic/valularfibrosis, 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
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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,