Histamine, Serotonin and Ergot Alkaloids
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Summary of chapter 16 of the book Basic and Clinical Pharmacology 12th ed by Katzung....
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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)
Pharmacodyanamics A. MECHANISM OF ACTION HISTAMINE RECEPTOR SUBTYPES Receptor Subtype
Location
Post receptor Mechanism
Partially Selective Agonist
Inverse Agonist
H1
SM, endothelium, brain
Gq, IP3, DAG
Histaprofiden
Mepyramine, triprolidine, cetirizine
H2
Gastric mucosa, cardiac muscle, mast cells, brain
Gs,
cAMP
Amthamine
Cimetidine, ranitidine, tiotidine
H3
Presynaptic autoreceptors & herereceptors; brain, myenteric plexus
Gi,
cAMp
R-αMethylhistamine, imetit,, immepip
Thioperamide, iodoprenpropit, clobenpropit,, tiprolisant
H4
Eosinophils, neutrophils, CD4 T cells
Gi,
cAMP
Clobenpropit, imetit, clozapine
Thioperamide
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
7.
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
1.
Sedation -
2.
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 -
3.
Motion sickness doxylamine (in bendectin) as treatment in the past
Antiparkinsonism effect -
4.
diphenhyramine
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
5.
6.
7.
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
urticaria
Chronic urticaria
Bronchial asthma
2.
Motion sickness & Vestibular disturbance
3.
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
PIPERAZINE DERIVATIVES
Hydroxyzine Cyclizine Meclizine
ALKLAMINES
Brompheniramine Chlorpheniramine
PHENOTHIAZINE
Promethazine
MISCELLANEOUS SECOND- GENERATION Cyproheptadine ANTIHISTAMINES
PIPERIDINE
Fexofenadine
MISCELLANEOUS
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
Distribution
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
Brain
Sumatrapin, elitriptan
5-HT 1E
Cortex, putamen
5-HT 1F
Cortex, hippocampus
LY3344864
5-HT 1P
Enteric nervous system
5Hydroxyindal apine
Partially selective antagonists WAY100635
Renzapride
5-HT 2A
Platelets, smooth muscle, cerebral cortex
a- methyl-5HT, DOI
Kentaserin
5-HT 2B
Stomach fundus
a- methyl-5-HT, DOI
RS127445
5-HT 2C
Choroid, hippocampus
a- methyl-5-HT, DOI, Lorcaserin
Mesulergine
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
GR1138080
5-HT 5A,B
Brain
5-HT 6,7
Brain
Clozapine(%HT7)
Tissue and Organ system effects Receptor subtype
Effects
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
Effects
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
Effects
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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