Download 16-Amine autacoids

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
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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
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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
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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
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)
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:
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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 in
some 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, 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
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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 5HT3 receptors that are inotropic receptors
Type
Distribution
Postulated Roles
5-HT1
Brain, instetinal nerves
Neuronal inhibition, behavioural
effects, cerebral vasoconstriction
5-HT2
Brain, heart, lungs, smooth muscle
control, 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,
Brain
6, 722/12/08 M Khattab
Not known
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)
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 Safety in pregnancy/lactation not tested
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
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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 -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
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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,
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