Histamine, Serotonin and Ergot Alkaloids

July 27, 2017 | Author: Steph Taylor Reyes Radan | Category: Serotonin, Receptor Antagonist, Neurochemistry, Pharmacology, Drugs
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Summary of chapter 16 of the book Basic and Clinical Pharmacology 12th ed by Katzung....


Chapter 16 Histamine, Serotonin, & the Ergot Alkaloids

Section IV: Drugs With Important Actions On Smooth Muscle  Histamine  Serotonin  Autacoid Groups Prostaglandins Endogenous peptides Leukotrienes

HISTAMINE Chemistry & Pharmacokinetics  2-(4-imidazolyl)ethylamine  Formed by decarboxylation of the amino acid L-histidine  found in plant and animal tissue and released from mast cells/ basophils as part of an allergic reaction  Its bound form are biologically inactive

Pharmacokinetics  Plays a role chemotaxis of white blood cells  Mast cells are especially numerous at sites of potential injury such as the nose, mouth, and feet, internal body surfaces and blood vessels.  Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter.  Histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.

Storage & Release of Histamines

Storage & Release of Histamines A. IMMUNOLOGIC RELEASE  IgE attachment to receptor  Degranulation Release of histamine, ATP, & other mediators

Type 1 allegic reactions: hayfever & acute urticaria

 Negative Feedback Control Mechanism Mediated by H2 receptor Histamine mediate its own release Exhibited by mast cells and basophils in skin of humans

limit the allergic reaction in the skin and blood

Storage & Release of Histamines B. CHEMICAL AND MECHANICAL RELEASE  HISTAMINE DISPLACERS (BOUND TO UNBOUND FORM)  morphines & tubocurine (Does not require energy to be released)  Loss of granules from mast cells, since Na displaces amines  Chemical & mast cells injuries

 Compound 48/80 (exocytotic degranulation/ requires energy & Ca+2)



Post receptor Mechanism

Partially Selective Agonist

Inverse Agonist


SM, endothelium, brain

Gq, IP3, DAG


Mepyramine, triprolidine, cetirizine


Gastric mucosa, cardiac muscle, mast cells, brain




Cimetidine, ranitidine, tiotidine


Presynaptic autoreceptors & herereceptors; brain, myenteric plexus



R-αMethylhistamine, imetit,, immepip

Thioperamide, iodoprenpropit, clobenpropit,, tiprolisant


Eosinophils, neutrophils, CD4 T cells



Clobenpropit, imetit, clozapine


Pharmacodynamics of Histamine B. TISSUE AND ORGAN EFFECTS 1. Nervous system  Powerful stimulant of sensory nerve endings ( pain & itching)  Local high concentration depolarize efferent (axonal) nerve endings  H1 receptors: modulates respiratory neuron signaling (inspiration & expiration)  H3 receptors: modulates release of several transmitters i.e. acetylcholine, amine and peptide transmitters in the brain

Pharmacodynamics of Histamine B. TISSUE AND ORGAN EFFECTS 2. Cardiovascular system •Injection or infusion: decrease systolic & diastolic pressureincrease heart rate •H1 receptor activation: Vasodilator action of histamine •Mediated by release of nitric oxide from the endothelium •Stimulatory action to the heart & reflex tachycardia

•H2 mediated cAMP •Histamine induced edema •Urticaria (hives) signals the release of histamine in the skin •Direct cardiac effects 1. H1: decreased contractility 2. H2: increased contractility and pacemaker rate

Pharmacodynamics of Histamine B. TISSUE AND ORGAN EFFECTS 3. Brionchiolar smooth muscles  Asthma patients: hyper-reactive neural response  Response to histamine is blocked by autonomic blocking drugs (ganglion blocking agents; H1 receptor antagonist)  Small doses of inhaled histamine: bronchial hyper-reactivity i.e. asthma & cystic fibrosis  metacholine provocation

Pharmacodynamics of Histamine B. TISSUE AND ORGAN EFFECTS 4. Gastrointestinal tract smooth muscles  Contraction of smooth muscles in gut  H1 receptor mediated  Guinea pigs ileum: standard bioassay for this amine

5. Other smooth muscle organs  No effect on eye  pregnant woman suffering from anaphylactic shock may end up aborting

Pharmacodynamics of Histamine B. TISSUE AND ORGAN EFFECTS 6. Secretory tissue  Activation of H2 receptors on gastric parietal cells: increase cAMP & Ca+2  Powerful stimulant of gastric acid secretion  Acetylcholine & gastrin do not increase cAMP


Metabolic Effects

Pharmacodynamics of Histamine B. TISSUE AND ORGAN EFFECTS 8. Triple response - Redspot, edema & flare response  Effects on 3 separate cell types ① Smooth muscle in the microcirculation

② Capillary or the venular endothelium ③ Sensory nerve endings

Clinical Pharmacology of Histamine Clinical Uses -

Provocative test or bronchial hyper reactivity

Toxicity and Contraindications -

Flushing, hypotension, tachycardia, wheals, bronchoconstriction, & gastrointestinal upset


Should not be administered to patients w/ asthma, ulcer disease, and gastrointestinal bleeding

Histamine Antagonist  Physiologic antagonist  Injection of epinephrine can be life saving in systemic anaphylaxis

 Release inhibitors  Reduce the degranulation of mast cells that result from immunologic triggering of antigen IgE  Cromolyn & nedocromyl

 Receptor antagonist  H2 receptor antagonist o burimamide: inhibit gastric stimulating activity of histamine o Therapy for peptic disease

 H3 & H4 o Not yet available for clinical use

Histamine Receptor Antagonists H1 Receptor Antagonist  Distinguished by relatively strong sedative effects:  1st Generation -

More likely to block autonomic receptors Stable amines Enter CNS rapidly Rapidly absorbed orally

 2nd Generation -

Less sedating; less bioavailability in the CNS Rapidly absorbed orally Metabolized by CYP3A4 4-6 hours duration of action after single dose Meclizine &others: longer acting 12-24hrs Less lipid soluble Substrates of P-glycoprotein transporter in the blood brain barrier

Figure. General structure of H1 antagonist drug

Histamine Receptor Antagonists H1 Receptor Antagonist: PHARMACODYNAMICS -

Both neutral H1 antagonist & inverse H1 agonist reduce/ block the action of histamine by reversible competitive binding Have negligible potency to H2 receptor and little at H3

Other actions of H1 receptor antagonist aside from blocking histamine


Result from similarity to structure of drugs that effect muscarinic cholinoreceptor, α-adrenoreceptor,, serotonin & other local anesthetic receptor site

Histamine Receptor Antagonists H1 Receptor Antagonist: PHARMACODYNAMICS Other actions of H1 receptor antagonist aside from blocking histamine


Sedation -


Resemble that of antimuscarinic drugs “sleep aids” Ordinary dosage: children manifest excitation rather than sedation Marked stimulation, agitation, convulsion at very high toxic levels

Antinausea and antiemetic actions -


Motion sickness doxylamine (in bendectin) as treatment in the past

Antiparkinsonism effect -



Anticholinoreceptor actions -

Fist generation agents i.e. ethonalamine & ethyldiamine Reported benefits for nonallergic rhinorrhea Causes urinary retention and blurred vision

Histamine Receptor Antagonists H1 Receptor Antagonist: PHARMACODYNAMICS Other actions of H1 receptor antagonist aside from blocking histamine




Adrenoceptor-blocking actions -

Phenothiazine subgroup i.e. promethazine


Cause orthostatic hypotension

Serotonin blocking action -

Observed in 1st generation H1 antagonist *cyproheptadine


Its structure resembles that of phenothiazine anhistamines


Potent H1 blocking agent

Local anesthesia -

Blocked Na channels in excitable membranes


Dipenhydramine & promethazine


Alternative to those allergic to conventional anesthetics

Histamine Receptor Antagonists H1 Receptor Antagonist: CLINICAL PHARMACOLOGY CLINICAL USES

1. Allergic reactions H1 ANTIHISTAMINES 1st Generation

2nd generation

Rhinitis (hay fever)

Allergic rhinitis


Chronic urticaria

Bronchial asthma


Motion sickness & Vestibular disturbance   


Scopalamine, fist generation H1 antagonist: dipenhydramine, piperazines (cyclizine & meclizine) Synergism w/ ephedrine & amphetamine more effective Menieres syndrome

Nausea and vomitting of pregnancy 

Piperazine derivatives (teratogenic effects), doxylamine (in Bectin) contains pyridoxine

Histamine Receptor Antagonists H1 Receptor Antagonist: CLINICAL PHARMACOLOGY CLINICAL USES: TOXICITY

   

Excitation and convulsions in children Postural hypotension Allergic responses Lethal venticular arrhythmias - Early administration of 2nd generation agents (tetrafenadine or aztemizole

Histamine Receptor Antagonists H1 antihistaminic drugs in clinical use FIRST- GENERATION ANTIHISTAMINES ETHANOLAMINES

Carbinoxamine (Clistin) Dimenhydrinate Diphenhydramine


Hydroxyzine Cyclizine Meclizine


Brompheniramine Chlorpheniramine







Loratidine Cetirizine

Histamine Receptor Antagonists H2 Receptor Antagonists    

Blocked gastric acid secretion with low toxicity Has no H1 agonist or antagonist effect Displays constitutive property; and are inverse agonists Over the counter drugs

H3 & H4 Receptor Antagonists  No selective drugs are presently available  H3 ligands: may be of value in sleep disorders, narcolepsy, obesity & cognitive & psychiatric disorders  Tiprolisant  H4 blockers: have potential in chronic inflammatory conditions: asthma; pruritus, allergic rhinitis, & pain conditions

Serotonin and Enteramine Serotonin - a vasoconstrictor (tonic) substance released from blood clot into the serum

Enteramine - smooth muscle stimulant in intestinal mucosa Identification of serotonin and enteramine in 1951 led to the synthesis of 5-hydroxytryptamine.

Serotonin  Neurotransmitter  Local hormone in the gut  Platelet clothing process  Migraine headache and several conditions (eg. Carcinoid syndrome)  Found in: *enterochromaffin cells in GIT (mammals), *platelets in the blood *raphe nuclei of the brainstem  Stored serotonins are depleted by reserpine

Biosynthesis of Serotonin and Melatonin Rate-limiting step:

Hydroxylation at C5 by tryptophan hydrolase 1 This can be blocked by pchlorophenylalanine (PCPA; fenclonine) and by pchloroamphetamine

Melatonin - a melanocyte-stimulating hormone

Serotonin receptor subtypes

Receptor subtypes


Partially selective agonists

5-HT 1A

Raphe nuclei, hippocampus

8-OH-DPAT, repinotan

5-HT 1B

Substantia nigra, globus pallidus, basal ganglia

Sumatrapin, L694247

5-HT 1D


Sumatrapin, elitriptan

5-HT 1E

Cortex, putamen

5-HT 1F

Cortex, hippocampus


5-HT 1P

Enteric nervous system

5Hydroxyindal apine

Partially selective antagonists WAY100635


5-HT 2A

Platelets, smooth muscle, cerebral cortex

a- methyl-5HT, DOI


5-HT 2B

Stomach fundus

a- methyl-5-HT, DOI


5-HT 2C

Choroid, hippocampus

a- methyl-5-HT, DOI, Lorcaserin


5-HT 3

Area postrema, sensory and enteric nerves

2-methyl-5-HT, mchlorophenylbi guanide

Granisetron, ondansetron

5-HT 4

CNS and myenteric neurons, smooth muscle

BIMU8, renzapride, metaclopramid e


5-HT 5A,B


5-HT 6,7



Tissue and Organ system effects Receptor subtype


Repitonan (5-HT 1A, agonist)

Antinociceptive action

5-HT 3

Vomiting reflex, chemoreceptive reflex

5-HT 1P and 5-HT 4

Enteric nervous system function

5-HT 2A

Effect on bronchiolar smooth muscle

5-HT 2

Contraction of vascular smooth muscle

Receptor subtype


5-HT 1A and 5-HT 7

Complex action

5-HT 4

Prokinetic effect

5-HT 1A, 5-HT 2, 5-HT 4

Normal cardiac development in fetus

5-HT 2B (agonist) 5-HT 2B (antagonist)

Associated with valvulopathy Prevent pulmonary hypertension

Serotonin syndrome - condition associated with skeletal muscle contractions and precipitated when MAO inhibitors are given with serotonin agonist

Clinical Pharmacology of Serotonin 

Buspirone (5-HT 1A agonist) – effective nonbenzodiazepine anxiolytic

Dexfenfluramine – selective 5HT agonist; appetite suppressant

Triptans (e.g sumtripan) – used for migraine headache

Valproic acid and topiramate - anticonvulsant

Propranolol, amitriptyline – for prophylaxis of migraine

Flunarizine – calcium channel blocker, prevent recurrences of migraine

Verapamil – modest efficacy as prophylaxis against migraine

Cisapride – 5-HT4 agonist, for gastroesophageal reflux and motility disorders

Tegaserod – 5-HT4 partial agonist, for irritable bowel syndromewith constipation

Fluoxentine – modulate serotogenic transmission

Serotonin antagonist 

Phenoxybenzamine  has a long lasting blocking action at 5-HT2 receptors.

Cyproheptadine  resembles the phenothiazine antihistaminic agents

Ketanserin  blocks 5-HT2 receptors on smooth muscle and other tissue

Ritanserin  5-HT2 antagonist has no or little alpha-blocking

Ondasentron  prototypical 5-HT3 antagonist

Ergot Alkaloids  Produced by Claviceps purpurea, fungus that infects grasses and grains

 Epidemics of ergot poisoning  ergotism  St. Anthony’s fire  ergot poisoning in medieval times named after the saint whose help was sought in relieving the burning pain of vasospastic ischema.

Chemistry and Pharmacokinetics  2 major families of compounds that incorporate nucleus Amine alkaloids Peptide alkaloids Ergot alkaloids are absorbed from GIT Amine alkaloids are absorbed in rectum and buccal cavity by administration with aerosol inhaler Primary metabolites- A ring, and peptide alkaloids

Organ System effects  Lysergic acid diethylamide (LSD) is synthetic ergot compounds; powerful hallucinogens.

 Bromocriptine, cabergoline and pergolide  have the highest selectivity for pituitary dopamine receptors. Supresses prolactin secretion from pituitary cells.

Clinical Pharmacology of Ergot Alkaloids Subclass

Mechanism of action


Clinical Applications

Pharmacokine-tics, Toxicities, Interactions

Vasoselective: Ergotamine

Mixed partial agonist effects at 5HT2 and alpha adrenoceptors

Causes marked smooth muscle contraction but blocks alpha agonist vasoconstriction

Migraine and cluster headache

Oral parenteralDuration 12-24h Toxicity- Prolonged vasospasm causing angina, gangrene, uterine spasm

Uteroselective: Ergonovine

Mixed partial agonist effects at 5HT2 and alpha adrenoceptors

Same as ergotamine Some selectivity for uterine smooth muscle

Postpartum bleeding Migraine headache

Oral, parenteral (methylyergonovine) Duration 2-4 h Toxicity- same as ergotamine

CNS selective: Lysergic acid diethylamide

Central nervous system (CNS) 5HT2 and dopamine agonist 5-HT2 agonist in periphery

Hallucinations Psychotomimetic

None widely abused

Oral Duration several h Toxicity- Prolonged psychotic state, flashbacks

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