16 Amine Autacoids

7/27/2019 16 Amine Autacoids

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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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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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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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16 Amine Autacoids