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

2. 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
22/12/08 M Khattab

3. 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
22/12/08 M Khattab

4. 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
22/12/08 M Khattab

5. 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

6. 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
22/12/08 M Khattab

7. 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

8. Histamine H1 Receptor Blockers (Antihistamines)
Ethanolamines:
Diphenhydramine, Dimenhydrinate*
Ethylenediamines:
Tripelennamine, antazoline, naphazoline
Alkylamines:
Chlorpheniramine, brompheniramine
Piperazines: Cyclizine*, meclizine*, cetrizine (2ndgeneration)
Phenothiazines: Promethazine
Piperidines: (New, Second-Generation)
Loratidine, desloratidine, fexofenadine
* Mainly used for prevention of nausea, vomiting & motion sickness
22/12/08 M Khattab

9. Antihistamines
Mechanism of Action: 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
22/12/08 M Khattab

10. 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

11. 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
22/12/08 M Khattab

12. 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
22/12/08 M Khattab

13. 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
22/12/08 M Khattab

14. 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
22/12/08 M Khattab

15. 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
22/12/08 M Khattab

16. 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

17. 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
22/12/08 M Khattab

18. 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
22/12/08 M Khattab

19. 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
22/12/08 M Khattab

20. 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
22/12/08 M Khattab

21. 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

22. 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
22/12/08 M Khattab

23. 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; retro-peritoneal & pulmonary fibrosis, aortic/valular fibrosis, insomnia, alopecia
Dose should be gradually tapered off for2-3 weeks to avoid rebound headache
22/12/08 M Khattab

24. 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

25. 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