22/12/08 M Khattab

Amine AutacoidsHistamine & 5-

Hydroxytryptamine

Dr Mahmoud Khattab

22/12/08 M Khattab

HistamineSource, 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

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

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

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 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

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 (2ndgeneration) Phenothiazines: Promethazine Piperidines: (New, Second-Generation) Loratidine, desloratidine, fexofenadine* Mainly used for prevention of nausea, vomiting & motion sickness

22/12/08 M Khattab

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

AntihistaminesPharmacological 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

AntihistaminesReceptors 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

AntihistaminesAdverse 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

AntihistaminesAdverse 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

AntihistaminesTherapeutic 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

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

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 5-HT3 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, 6, 7

Brain Not known

22/12/08 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

22/12/08 M Khattab

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

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

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 AntagonistsErgot 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

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

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,